respiratory disorders
by subbia1988
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1. asthma

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ASTHMA - E. R. McFadden, Jr.

INTRODUCTION

Asthma is defined as a chronic inflammatory disease of airways that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli. It is manifested physiologically by a widespread narrowing of the air passages, which may be relieved spontaneously or as a result of therapy, and clinically by paroxysms of dyspnea, cough, and wheezing. Asthma is an episodic disease, with acute exacerbations interspersed with symptom-free periods. Typically, most attacks are short-lived, lasting minutes to hours, and clinically the patient seems to recover completely after an attack. However, there can be a phase in which the patient experiences some degree of airway obstruction daily. This phase can be mild, with or without superimposed severe episodes, or much more serious, with severe obstruction persisting for days or weeks; the latter condition is known as status asthmaticus. In unusual circumstances, acute episodes can cause death.

PREVALENCE AND ETIOLOGY

Asthma is a very common disease with immense social impact. The prevalence of asthma is rising in many parts of the world, but it is unclear whether this is due to an actual increase in incidence or merely to the fact that the size of the overall population is growing. It is estimated that 4 to 5% of the population of the United States is affected. Data from the Centers for Disease Control and Prevention suggest that 10 to 11 million persons had acute attacks in 1998, which resulted in 13.9 million outpatient visits, 2 million requests for urgent care, and 423,000 hospitalizations, with a total cost $6 billion. The impact of the disease appears to fall more heavily on minorities and inner-city African-American and Hispanic persons.

Bronchial asthma occurs at all ages but predominantly in early life. About one-half of cases develop before age 10, and another third occur before age 40. In childhood, there is a 2:1 male/female preponderance, but the sex ratio equalizes by age 30. From an etiologic standpoint, asthma is a heterogeneous disease and genetic (atopic) and environmental factors, such as viruses, occupational exposures, and allergens, contribute to its initiation and continuance.

Atopy is the single largest risk factor for the development of asthma. Allergic asthma is often associated with a personal and/or family history of allergic diseases such as rhinitis, urticaria, and eczema; with positive wheal-and-flare skin reactions to intradermal injection of extracts of airborne antigens; with increased levels of IgE in the serum; and/or with a positive response to provocation tests involving the inhalation of specific antigen.

A significant fraction of patients with asthma present with no personal or family history of allergy, with negative skin tests, and with normal serum levels of IgE, and therefore have disease that cannot be classified on the basis of currently defined immunologic mechanisms. These patients are said to have idiosyncratic asthma or nonatopic asthma. Many patients have disease that does not fit clearly into either of the preceding categories but instead falls into a mixed group with features of each. In general, asthma that has its onset in early life tends to have a strong allergic component, whereas asthma that develops late tends to be nonallergic or to have a mixed etiology.

PATHOGENESIS (SEE ALSO CHAP. 298)

Asthma results from a state of persistent subacute inflammation of the airways. Even in asymptomatic patients, the airways can be edematous and infiltrated with eosinophils, neutrophils, and lymphocytes, with or without an increase in the collagen content of the epithelial basement membrane. Overall, there is a generalized increase in cellularity associated with an elevated capillary density. There may also be glandular hypertrophy and denudation of the epithelium. These changes may persist despite treatment and often do not relate to the severity of the disease.

The physiologic and clinical features of asthma derive from an interaction among the resident and infiltrating inflammatory cells in the airway surface epithelium, inflammatory mediators, and cytokines. The cells thought to play important parts in the inflammatory response are mast cells, eosinophils, lymphocytes, and airway epithelial cells. The roles of neutrophils, macrophages, and other cellular constituents of the airways are less well defined. Each of the major cell types can contribute mediators and cytokines to initiate and amplify both acute inflammation and the long-term pathologic changes described (Fig. 236-1). The mediators released produce an intense, immediate inflammatory reaction involving bronchoconstriction, vascular congestion, edema formation, increased mucus production, and impaired mucociliary transport. This intense local event can then be followed by a more chronic one. Other elaborated chemotactic factors (eosinophil and neutrophil chemotactic factors of anaphylaxis and leukotriene B4) also bring eosinophils, platelets, and polymorphonuclear leukocytes to the site of the reaction. The airway epithelium is both the target of, and a contributor to, the inflammatory cascade. This tissue both amplifies bronchoconstriction and promotes vasodilatation through the release of the compounds shown in Fig. 236-2.

The eosinophil appears to play an important part in the infiltrative component. Interleukin (IL) 5 stimulates the release of these cells into the circulation and extends their survival. Once activated, these cells are a rich source of leukotrienes, and the granular proteins released (major basic protein and eosinophilic cationic protein) and oxygen-derived free radicals are capable of destroying the airway epithelium, which then is sloughed into the bronchial lumen in the form of Creola bodies. Besides resulting in a loss of barrier and secretory function, such damage elicits the production of chemotactic cytokines, leading to further inflammation. In theory, it can also expose sensory nerve endings, thus initiating neurogenic inflammatory pathways. That, in turn, could convert a primary local event into a generalized reaction via a reflex mechanism. Although an important element in inflammation, the role that the eosinophil plays in establishing and maintaining airway hyperresponsiveness is undergoing reevaluation. Studies using antibodies against IL-5 show a disassociation between the inflammatory and physiologic events following an antigen challenge and blood and sputum eosinophilia. The cytokine network possibly involved in asthma is shown in Fig. 236-3.

T lymphocytes also appear to be important in the inflammatory response. Activated TH2 cells are present in increased numbers in asthmatic airways and produce cytokines such as IL1-4 that initiate humoral (IgE) immune responses. They also elaborate IL-5 with its effect on eosinophils. Data are accumulating that asthma may be related to an imbalance between TH1 and TH2 immune responses, but firm conclusions are not yet available.

GENETIC CONSIDERATIONS

Although there is little doubt that asthma has a strong familial component, the identification of the genetic mechanisms underlying the illness has proven difficult for such fundamental reasons as a lack of uniform agreement on the definition of the disease, the inability to define a single phenotype, non-Mendelian modes of inheritance, and an incomplete understanding of how environmental factors modify genetic expression. Screening families for candidate genes has identified multiple chromosomal regions that relate to atopy, elevated IgE levels, and airway hyperresponsiveness. Evidence for genetic linkage of high total serum IgE levels and atopy has been observed on chromosomes 5q, 11q, and 12q in a number of populations scattered throughout the world. Regions of the genome demonstrating evidence for linkage to bronchial hyperreactivity also typically show evidence for linkage to elevated total serum IgE levels. Excellent candidate genes exist for specific abnormalities in asthma within the regions that were identified in the linkage studies. For example, chromosome 5q contains cytokine clusters including IL1-4, IL-5, IL-9, and IL-13. Other regions on chromosome 5q also contain the ß-adrenergic receptors and the glucocorticoid receptors. Chromosome 6p contains regions that are important in antigen presentation and mediation of the inflammatory response. Chromosome 12q contains two genes that could influence atopy and airway hyperresponsiveness, including nitric oxide synthase.

STIMULI THAT INCITE ASTHMA

The stimuli that incite acute episodes of asthma can be grouped into seven major categories: allergenic, pharmacologic, environmental, occupational, infectious, exercise-related, and emotional.

Allergens Allergic asthma is dependent on an IgE response controlled by T and B lymphocytes and activated by the interaction of antigen with mast cell-bound IgE molecules. The airway epithelium and submucosa contain dendritic cells that capture and process antigen. After taking up an immunogen, these cells migrate to the local lymph nodes where they present the material to T cell receptors. In the appropriate genetic setting, the interaction of antigen with a naive T cell THO in the presence of IL1-4 leads to the differentiation of the cell to a TH2 subset. This process not only helps facilitate the inflammation of asthma but also causes B lymphocytes to switch their antibody production from IgG and IgM to IgE.

Once synthesized and released by B cells, IgE circulates in the blood until it attaches to high-affinity receptors on mast cells and low-affinity receptors on basophils. Most of the allergens that provoke asthma are airborne, and to induce a state of sensitivity they must be reasonably abundant for considerable periods of time. Once sensitization has occurred, however, the patient can exhibit exquisite responsivity, so that minute amounts of the offending agent can produce significant exacerbations of the disease. Immune mechanisms appear to be causally related to the development of asthma in 25 to 35% of all cases and to be contributory in perhaps another third. Higher prevalences have been suggested, but it is difficult to know how to interpret the data because of confounding factors. Allergic asthma is frequently seasonal, and it is most often observed in children and young adults. A nonseasonal form may result from allergy to feathers, animal danders, dust mites, molds, and other environmental antigens that are present continuously. Exposure to antigen typically produces an immediate response in which airway obstruction develops in minutes and then resolves. In 30 to 50% of patients, a second wave of bronchoconstriction, the so-called late reaction, develops 6 to 10 h later. In a minority, only a late reaction occurs. It was formerly thought that the late reaction was essential to the development of the increase in airway reactivity that follows antigen exposure. This is now known not to be the case.

The mechanism by which an inhaled allergen provokes an acute episode of asthma depends in part on antigen-antibody interactions on the surface of pulmonary mast cells, with the subsequent generation and release of the mediators of immediate hypersensitivity. Current hypotheses hold that very small antigenic particles penetrate the lung's defenses and come in contact with mast cells that interdigitate with the epithelium at the luminal surface of the central airways. The subsequent elaboration of mediators and cytokines then produces the sequence outlined above.

Pharmacologic Stimuli The drugs most commonly associated with the induction of acute episodes of asthma are aspirin, coloring agents such as tartrazine, ß-adrenergic antagonists, and sulfiting agents. It is important to recognize drug-induced bronchial narrowing because its presence is often associated with great morbidity. Furthermore, death sometimes has followed the ingestion of aspirin (or other nonsteroidal anti-inflammatory agents) or ß-adrenergic antagonists. The typical aspirin-sensitive respiratory syndrome primarily affects adults, although the condition may occur in childhood. This problem usually begins with perennial vasomotor rhinitis that is followed by a hyperplastic rhinosinusitis with nasal polyps. Progressive asthma then appears. On exposure to even very small quantities of aspirin, affected individuals typically develop ocular and nasal congestion and acute, often severe episodes of airways obstruction.

The prevalence of aspirin sensitivity in patients with asthma varies from study to study, but many authorities feel that 10% is a reasonable figure. There is a great deal of cross-reactivity between aspirin and other nonsteroidal anti-inflammatory compounds that inhibit prostaglandin G/H synthase 1 (cyclooxygenase type 1). Indomethacin, fenoprofen, naproxen, zomepirac sodium, ibuprofen, mefenamic acid, and phenylbutazone are particularly important in this regard. However, acetaminophen, sodium salicylate, choline salicylate, salicylamide, and propoxyphene are well tolerated. The exact frequency of cross-reactivity to tartrazine and other dyes in aspirin-sensitive individuals with asthma is also controversial; again, 10% is the commonly accepted figure. This peculiar complication of aspirin-sensitive asthma is particularly insidious, however, in that tartrazine and other potentially troublesome dyes are widely present in the environment and may be unknowingly ingested by sensitive patients.

Patients with aspirin sensitivity can be desensitized by daily administration of the drug. After this form of therapy, cross-tolerance also develops to other nonsteroidal anti-inflammatory agents. The mechanism by which aspirin and other such drugs produce bronchospasm appears to be a chronic overexcretion of cysteinyl leukotrienes, which activate mast cells. The adverse reaction to aspirin can be inhibited with the use of leukotriene synthesis blockers or receptor antagonists.

ß-Adrenergic antagonists regularly obstruct the airways in individuals with asthma as well as in others with heightened airway reactivity and should be avoided by such individuals. Even the selective beta1 agents have this propensity, particularly at higher doses. In fact, the local use of beta1 blockers in the eye for the treatment of glaucoma has been associated with worsening asthma.

Sulfiting agents, such as potassium metabisulfite, potassium and sodium bisulfite, sodium sulfite, and sulfur dioxide, which are widely used in the food and pharmaceutical industries as sanitizing and preserving agents, can also produce acute airway obstruction in sensitive individuals. Exposure usually follows ingestion of food or beverages containing these compounds, e.g., salads, fresh fruit, potatoes, shellfish, and wine. Exacerbation of asthma has been reported after the use of sulfite-containing topical ophthalmic solutions, intravenous glucocorticoids, and some inhalational bronchodilator solutions. The incidence and mechanism of action of this phenomenon are unknown. When suspected, the diagnosis can be confirmed by either oral or inhalational provocations.

Environment and Air Pollution (See also Chap. 238) Environmental causes of asthma are usually related to climatic conditions that promote the concentration of atmospheric pollutants and antigens. These conditions tend to develop in heavily industrial or densely populated urban areas and are frequently associated with thermal inversions or other situations creating stagnant air masses. In these circumstances, although the general population can develop respiratory symptoms, patients with asthma and other respiratory diseases tend to be more severely affected. The air pollutants known to have this effect are ozone, nitrogen dioxide, and sulfur dioxide. All produce greater effects during periods of high ventilation. In some regions of North America, seasonal concentrations of airborne antigens such as pollen can rise high enough to result in epidemics of asthma admissions to hospitals and an increase in the death rate. These events may be ameliorated by treating patients prophylactically with anti-inflammatory drugs before the allergy season begins.

Occupational Factors (See also Chap. 238) Occupation-related asthma is a significant health problem, and acute and chronic airway obstruction have been reported to follow exposure to a large number of compounds used in many types of industrial processes. In general, the agents can be classified into high-molecular-weight compounds, which are believed to induce asthma through immunologic mechanisms, and low-molecular-weight agents, which serve as haptines or can release bronchoconstrictor substances. High-molecular-weight compounds of importance are wood and vegetable dusts (e.g., those of oak, grain, flour, castor bean, green coffee bean, mako, gum acacia, karay, gum, and tragacanth), pharmaceutical agents (e.g., antibiotics, piperazine, and cimetidine), biologic enzymes (e.g., laundry detergents, pancreatic enzymes, and Bacillus subtilis), and animal and insect dusts, serums, and secretions (e.g., laboratory animals, chickens, crabs, prawns, oysters, flys, bees, and moths). Troublesome low-molecular-weight compounds are metal salts (e.g., platinum, chrome, vanadium, and nickel) and industrial chemicals and plastics (e.g., toluene diisocyanate, phthalic acid anhydride, trimellitic anhydride, persulfates, ethylenediamine, p-phenylenediamine, western red cedar, azidrocarbonamide, and various dyes). Formaldehyde and urea formaldehyde also fall into this group. It is important to recognize that exposure to sensitizing chemicals, particularly those used in paints, solvents, and plastics, can also occur during leisure or non-work-related activities.

If the occupational agent causes an immediate or dual immunologic reaction, the history is similar to that which occurs with exposure to other antigens. Often, however, patients will give a characteristic cyclic history. They are well when they arrive at work, and symptoms develop toward the end of the shift, progress after the work site is left, and then regress. Absence from work during weekends or vacations brings about remission. Frequently, there are similar symptoms in fellow employees.

Infections Respiratory infections are the most common of the stimuli that evoke acute exacerbations of asthma. Respiratory viruses and not bacteria or allergy to microorganisms are the major etiologic factors. In young children, the most important infectious agents are respiratory syncytial virus and parainfluenza virus. In older children and adults, rhinovirus and influenza virus predominate as pathogens. Simple colonization of the tracheobronchial tree is insufficient to evoke acute episodes of bronchospasm, and attacks of asthma occur only when symptoms of an ongoing respiratory tract infection are, or have been, present. Viral infections can actively and chronically destabilize asthma, and they are perhaps the only stimuli that can produce constant symptoms for weeks. The mechanism by which viruses induce exacerbations of asthma may be related to the production of T cell-derived cytokines that potentiate the infiltration of inflammatory cells into already susceptible airways.

Exercise Exercise is a very common precipitant of acute episodes of asthma. This stimulus differs from other naturally occurring provocations, such as antigens, viral infections, and air pollutants, in that it does not evoke any long-term sequelae, nor does it increase airway reactivity. Typically the attacks follow exertion and do not occur during it. The critical variables that determine the severity of the postexertional airway obstruction are the levels of ventilation achieved and the temperature and humidity of the inspired air. The higher the ventilation and the lower the heat content of the air, the greater the response. For the same inspired air conditions, running produces a more severe attack of asthma than walking because of its greater ventilatory cost. Conversely, for a given task, the inhalation of cold air markedly enhances the response, while warm, humid air blunts or abolishes it. Consequently, activities such as ice hockey, cross-country skiing, and ice skating (high ventilations of cold air) are more provocative than is swimming in an indoor, heated pool (relatively low ventilation of humid air). The mechanism by which exercise produces obstruction may be related to a thermally produced hyperemia and capillary leakage in the airway wall.

Emotional Stress Psychological factors can worsen or ameliorate asthma. Changes in airway caliber seem to be mediated through modification of vagal efferent activity, but endorphins may also play a role. The extent to which psychological factors participate in the induction and/or continuation of any given acute exacerbation is not established but probably varies from patient to patient and in the same patient from episode to episode.

PATHOLOGY

In a patient who has died of acute asthma, the most striking feature of the lungs at necropsy is their gross overdistention and failure to collapse when the pleural cavities are opened. When the lungs are cut, numerous gelatinous plugs of exudate are found in most of the bronchial branches down to the terminal bronchioles. Histologic examination shows hypertrophy of the bronchial smooth muscle, hyperplasia of mucosal and submucosal vessels, mucosal edema, denudation of the surface epithelium, pronounced thickening of the basement membrane, and eosinophilic infiltrates in the bronchial wall. There is an absence of any of the well-recognized forms of destructive emphysema.

PATHOPHYSIOLOGY

The pathophysiologic hallmark of asthma is a reduction in airway diameter brought about by contraction of smooth muscle, vascular congestion, edema of the bronchial wall, and thick, tenacious secretions. The net result is an increase in airway resistance, a decrease in forced expiratory volumes and flow rates, hyperinflation of the lungs and thorax, increased work of breathing, alterations in respiratory muscle function, changes in elastic recoil, abnormal distribution of both ventilation and pulmonary blood flow with mismatched ratios, and altered arterial blood gas concentrations. Thus, although asthma is considered to be primarily a disease of airways, virtually all aspects of pulmonary function are compromised during an acute attack. In addition, in very symptomatic patients there frequently is electrocardiographic evidence of right ventricular hypertrophy and pulmonary hypertension. When a patient presents for therapy, the 1-s forced expiratory volume (FEV1) or peak expiratory flow rate (PEFR) is typically 40% of predicted. In keeping with the alterations in mechanics, the associated air trapping is substantial. In acutely ill patients, residual volume frequently approaches 400% of normal, while functional residual capacity doubles.

Hypoxia is a universal finding during acute exacerbations, but frank ventilatory failure is relatively uncommon, being observed in 10 to 15% of patients presenting for therapy. Most individuals with asthma have hypocapnia and a respiratory alkalosis. In acutely ill patients, the finding of a normal arterial carbon dioxide tension tends to be associated with quite severe levels of obstruction. Consequently, when found in a symptomatic individual, it should be viewed as representing impending respiratory failure, and the patient should be treated accordingly. Equally, the presence of metabolic acidosis in the setting of acute asthma signifies severe obstruction. Cyanosis is a very late sign. Trying to judge the state of an acutely ill patient's ventilatory status on clinical grounds alone can be extremely hazardous, and clinical indicators should not be relied on with any confidence. Therefore, in patients with suspected alveolar hypoventilation, arterial blood gas tensions must be measured.

CLINICAL FEATURES

The symptoms of asthma consist of a triad of dyspnea, cough, and wheezing, the last often being regarded as the sine qua non. In its most typical form, all three symptoms coexist. At the onset of an attack, patients experience a sense of constriction in the chest, often with a nonproductive cough. Respiration becomes audibly harsh; wheezing in both phases of respiration becomes prominent; expiration becomes prolonged; and patients frequently have tachypnea, tachycardia, and mild systolic hypertension. The lungs rapidly become overinflated, and the anteroposterior diameter of the thorax increases. If the attack is severe or prolonged, there may be a loss of adventitial breath sounds, and wheezing becomes very high pitched. Furthermore, the accessory muscles become visibly active, and a paradoxical pulse often develops. These two signs are extremely valuable in indicating the severity of the obstruction. In the presence of either, pulmonary function tends to be significantly more impaired than in their absence. It is important to note that the development of a paradoxical pulse depends on the generation of large negative intrathoracic pressures. Thus, if the patient's breathing is shallow, this sign and/or the use of accessory muscles could be absent even though obstruction is quite severe. The other signs and symptoms of asthma only imperfectly reflect the physiologic alterations that are present. Indeed, if the disappearance of subjective complaints or even of wheezing is used as the end point at which therapy for an acute attack is terminated, an enormous reservoir of residual disease will be missed.

The end of an episode is frequently marked by a cough that produces thick, stringy mucus, which often takes the form of casts of the distal airways (Curschmann's spirals) and, when examined microscopically, often shows eosinophils and Charcot-Leyden crystals. In extreme situations, wheezing may lessen markedly or even disappear, cough may become extremely ineffective, and the patient may begin a gasping type of respiratory pattern. These findings imply extensive mucus plugging and impending suffocation. Ventilatory assistance by mechanical means may be required. Atelectasis due to inspissated secretions occasionally occurs with asthmatic attacks. Spontaneous pneumothorax and/or pneumomediastinum occur but are rare.

Less typically, a patient with asthma may complain of intermittent episodes of nonproductive cough or exertional dyspnea. Unlike other individuals with asthma, when these patients are examined during symptomatic periods, they tend to have normal breath sounds but may wheeze after repeated forced exhalations and/or may show ventilatory impairments when tested in the laboratory. In the absence of both these signs, a bronchoprovocation test may be required to make the diagnosis.

DIFFERENTIAL DIAGNOSIS

The differentiation of asthma from other diseases associated with dyspnea and wheezing is usually not difficult, particularly if the patient is seen during an acute episode. The physical findings and symptoms listed above and the history of periodic attacks are quite characteristic. A personal or family history of allergic diseases such as eczema, rhinitis, or urticaria is valuable contributory evidence. An extremely common feature of asthma is nocturnal awakening with dyspnea and/or wheezing. In fact, this phenomenon is so prevalent that its absence raises doubt about the diagnosis.

Upper airway obstruction by tumor or laryngeal edema can occa-sionally be confused with asthma. Typically, a patient with such a condition will present with stridor, and the harsh respiratory sounds can be localized to the area of the trachea. Representative flow-volume curves are shown in Fig. 236-4. Diffuse wheezing throughout both lung fields is usually absent. However, differentiation can sometimes be difficult, and indirect laryngoscopy or bronchoscopy may be required. Asthma-like symptoms have been described in patients with glottic dysfunction. These individuals narrow their glottis during inspiration and expiration, producing episodic attacks of severe airway obstruction. Occasionally, carbon dioxide retention develops. However, unlike in asthma, the arterial oxygen tension is well preserved, and the alveolar-arterial gradient for oxygen narrows during the episode, instead of widening as with lower airway obstruction. To establish the diagnosis of glottic dysfunction, the glottis should be examined when the patient is symptomatic. Normal findings at such a time exclude the diagnosis; normal findings during asymptomatic periods do not.

Persistent wheezing localized to one area of the chest in association with paroxysms of coughing indicates endobronchial disease such as foreign-body aspiration, a neoplasm, or bronchial stenosis.

The signs and symptoms of acute left ventricular failure occasionally mimic asthma, but the findings of moist basilar rales, gallop rhythms, blood-tinged sputum, and other signs of heart failure (Chap. 216) allow the appropriate diagnosis to be reached.

Recurrent episodes of bronchospasm can occur with carcinoid tumors (Chap. 329), recurrent pulmonary emboli (Chap. 244), and chronic bronchitis (Chap. 242). In chronic bronchitis there are no true symptom-free periods, and one can usually obtain a history of chronic cough and sputum production as a background on which acute attacks of wheezing are superimposed. Recurrent emboli can be very difficult to separate from asthma. Frequently, patients with this condition present with episodes of breathlessness, particularly on exertion, and they sometimes wheeze. Lung scans may not be diagnostic because of the ventilation-perfusion abnormalities characteristic of asthma, and pulmonary angiography may be necessary to establish the correct diagnosis.

Eosinophilic pneumonias (Chap. 237) are often associated with asthmatic symptoms, as are various chemical pneumonias and exposures to insecticides and cholinergic drugs. Bronchospasm is occasionally a manifestation of systemic vasculitis with pulmonary involvement.

DIAGNOSIS

The diagnosis of asthma is established by demonstrating reversible airway obstruction. Reversibility is traditionally defined as a =15% increase in FEV12 after two puffs of a ß-adrenergic agonist. When the spirometry results are normal at presentation, the diagnosis can be made by showing heightened airway responsiveness to challenges with histamine, methacholine, or isocapnic hyperventilation of cold air. Once the diagnosis is confirmed, the course of the illness and the effectiveness of therapy can be followed by measuring PEFRs3 at home and/or the FEV1 in the office or laboratory. Positive wheal-and-flare reactions to skin tests can be demonstrated to various allergens, but such findings do not necessarily correlate with the intrapulmonary events. Sputum and blood eosinophilia and measurement of serum IgE levels are also helpful but are not specific for asthma. Chest roentgenograms showing hyperinflation are also nondiagnostic.

TREATMENT

Elimination of the causative agent(s) from the environment of an allergic individual with asthma is the most successful means available for treating this condition (for details on avoidance, see Chap. 298). Desensitization or immunotherapy with extracts of the suspected allergens has enjoyed widespread favor, but controlled studies are limited and have not proved to be highly effective.

DRUG TREATMENT The available agents for treating asthma can be divided into two general categories: drugs that inhibit smooth-muscle contraction, i.e., the so-called "quick relief medications" (ß-adrenergic agonists, methylxanthines, and anticholinergics) and agents that prevent and/or reverse inflammation, i.e., the "long-term control medications" (glucocorticoids, long-acting ß2-agonists, combined medications, mast cell-stabilizing agents, leukotriene modifiers, and methylxanthines (Table 236-1).

Quick Relief Medications • ADRENERGIC STIMULANTS The drugs in this category consist of the catecholamines, resorcinols, and saligenins. These agents produce airway dilation through stimulation of ß-adrenergic receptors and activation of G proteins with the resultant formation of cyclic adenosine monophosphate (AMP). They also decrease release of mediators and improve mucociliary transport. The catecholamines (epinephrine, isoproterenol, and isoetharine) are short-acting (30 to 90 min) and are effective only when administered by inhalational or parenteral routes. Their use has been superceded by the longer acting selective ß2-agonists terbutaline, fenoterol (a resorsinol), and albuterol (a saligenin). The resorsinols and saligenins are highly selective for the respiratory tract and are virtually devoid of significant cardiac effects except at high doses.

Their major side effect is tremor. They are active by all routes of administration and are relatively long-lasting (4 to 6 h). Inhalation is the preferred route because it allows maximal bronchodilation with fewer side effects. In treating episodes of severe asthma, intravenous administration offers no advantages over the inhaled route.

Very long lasting compounds (salmeterol and formoterol) are available and provide sustained effects for 9 to 12 h (Table 236-1). They are particularly helpful for conditions such as nocturnal and exercise-induced asthma. Salmeterol is not recommended for the treatment of acute episodes because of its relatively slow onset of action (~30 min), nor is it intended as a rescue drug for breakthrough symptoms. In addition, its long half-life means that administration of extra doses can cause cumulative side effects. The limits to the use of formoterol are not yet fully established. These compounds are now thought of as long-term controller medications by some, presumably because of their anti-inflammatory activities. The clinical significance of this aspect of their pharmacology has yet to be completely elucidated.

METHYLXANTHINES Theophylline and its various salts are medium-potency bronchodilators with questionable anti-inflammatory properties. The therapeutic plasma concentrations of theophylline lie between 5 and 15 ug/mL. The dose required to achieve the desired level varies widely from patient to patient owing to differences in the metabolism of the drug. Clearance falls with age and the concurrent use of erythromycin and other macrolide antibiotics, the quinolone antibiotics, and troleandomycin, allopurinol, cimetidine, and propranolol. It rises with use of cigarettes, marijuana, phenobarbital, phenytoin, or any other drug that is capable of inducing hepatic microsomal enzymes.

For maintenance therapy, long-acting theophylline compounds are available and are usually given once or twice daily. The dose is adjusted on the basis of the clinical response with the aid of serum theophylline measurements. Single-dose administration in the evening reduces nocturnal symptoms and helps keep the patient complaint-free during the day. However, the methylxanthines can disrupt sleep architecture. They are now considered second-line therapy, and as such they are rarely used in acute situations and infrequently in chronic ones. There is minimal evidence for additional benefit when used with optimal doses of ß-adrenergics. There are some data that the methylxanthines can decrease inflammation, but as with the long-acting ß2-agonists, the effect is not large and its clinical impact is undefined. Nonetheless, some authorities now place these compounds in the "controller" class (Fig. 236-1). The most common side effects are nervousness, nausea, vomiting, anorexia, and headache. At plasma levels 30 ug/mL there is a risk of seizures and cardiac arrhythmias.

ANTICHOLINERGICS Anticholinergic drugs such as ipratropium bromide have been found to be both effective and free of untoward effects. They may be of particular benefit for patients with coexistent heart disease, in whom the use of methylxanthines and ß-adrenergic stimulants may be dangerous. The major disadvantages of the anticholinergics are that they are slow to act (60 to 90 min may be required before peak bronchodilation is achieved) and they are of only modest potency.

Long-Term Controller Medications (Table 236-1) • GLUCOCORTICOIDS Glucocorticoids are the most potent and most effective anti-inflammatory medications available. Systemic or oral steroids are most beneficial in acute illness, when severe airway obstruction is not resolving or is worsening despite intense optimal bronchodilator therapy, and in chronic disease, when there has been failure of a previously optimal regimen with frequent recurrences of symptoms of increasing severity. Inhaled glucocorticoids are used in the long-term control of asthma.

Glucocorticoids are not bronchodilators, and the correct dose to use in acute situations is a matter of debate. In the United States, the recommended starting dose is 120 to 180 mg of methylprednisolone intravenously every 6 h. Since intravenous and oral administration produce the same effects, prednisone, 60 mg every 6 h, can be substituted. Clinical impressions suggest that smaller quantities may work as effectively, but there are no confirmatory data. In the United Kingdom and elsewhere, acute asthma both in and out of hospital is frequently treated with doses of prednisolone ranging from 30 to 40 mg given once daily. It should be emphasized that the effects of steroids in acute asthma are not immediate and may not be seen for =6 h after the initial administration. Consequently, it is mandatory to continue vigorous bronchodilator therapy during this interval.

Some believe that glucocorticoids should be given to all acutely ill patients upon presentation because of their long delay to peak effect. While there is some merit to this argument, glucocorticoids are often not necessary; the symptoms of ~80% of patients seen in emergency departments resolve rapidly with only inhaled ß-agonists. Those who need steroids can be rapidly identified by monitoring their PEFR3. Irrespective of the regimen chosen, it is important to appreciate that rapid tapering of glucocorticoids frequently results in recurrent obstruction. Most authorities recommend reducing the dose by one-half every third to fifth day, over 10 to 12 days, after an acute episode. Beyond this point, the drug can be abruptly stopped. In situations in which it appears that continued steroid therapy is needed, an alternate-day schedule should be instituted to minimize side effects. This is particularly important in children, since continuous glucocorticoid administration interrupts growth. Long-acting preparations such as dexamethasone should not be used in this approach, for they defeat the purpose of alternate-day schedules by causing prolonged suppression of the pituitary-adrenal axis. The availability of inhaled agents has all but eliminated the need for this form of therapy. The usual doses of oral glucocorticoids for nonemergent episodes of asthma are summarized in Table 236-1.

Inhaled Glucocorticoids These drugs are indicated in patients with persistent symptoms. The agents currently available in the United States and their comparative doses are presented in Table 236-2. These drugs share the ability to control inflammation, facilitate the long-term prevention of symptoms, reduce the need for oral glucocorticoids, minimize acute occurrences, and prevent hospitalizations.

There is no fixed dose of inhaled steroid that works for all patients. Requirements are dictated by the response of the individual and wax and wane in concert with progression of the disease. Generally, the worse the patient's condition, the more inhaled steroid is needed to gain control. Once achieved, however, remission can often be maintained with quantities as low as one or two puffs/day. Inhaled steroids can take up to a week or more to produce improvements; consequently, in rapidly deteriorating situations, it is best to prescribe oral preparations and initiate inhaled drugs as the dose of the former is reduced. In less emergent circumstances, the quantity of inhaled drug can be increased up to 2 to 2.5 times the recommended starting doses. The side effects increase in proportion to the dose-time product. In addition to thrush and dysphonia, the increased systemic absorption that accompanies larger doses of inhaled steroids has been reported to produce adrenal suppression, cataract formation, decreased growth in children, interference with bone metabolism, and purpura. As is the case with oral agents, suppression of inflammation, per se, cannot be relied upon to provide optimal results. It is essential to continue adrenergic or methylxanthine bronchodilators if the patient's disease is unstable. The combination of a long acting ß-agonist and inhaled steroid seems particularly efficacious in patients with mild to moderate disease.

COMBINED MEDICATIONS The combination of an inhaled steroid and a long-acting ß2 agonist is gaining popularity. The only such combination available in the United States at present is fluticasone and salmeterol. Other combinations are being tested but are not yet available. There is little question that combinations of agents add a significant degree of convenience in the care of chronic asthma. They tend to work best in patients with milder disease. It has been suggested that the combination provides better pharmacologic activity than the individual drugs given alone.

MAST CELL-STABILIZING AGENTS Cromolyn sodium and nedocromil sodium do not influence airway tone. Their major therapeutic effect is to inhibit the degranulation of mast cells, thereby preventing the release of the chemical mediators of anaphylaxis.

Cromolyn sodium and nedocromil sodium, like the inhaled steroids, improve lung function, reduce symptoms, and lower airway reactivity in persons with asthma. They are most effective in atopic patients who have either seasonal disease or perennial airway stimulation. A therapeutic trial of two puffs four times daily for 4 to 6 weeks is frequently necessary before the beneficial effects of the drug appear. Unlike steroids, nedocromil and cromolyn sodium, when given prophylactically, block the acute obstructive effects of exposure to antigen, industrial chemicals, exercise, or cold air. With antigen, the late response is also abolished. Therefore, a patient who has intermittent exposure to either antigenic or nonantigenic stimuli that provoke acute episodes of asthma need not use these drugs continuously but instead can obtain protection by taking the drug only 15 to 20 min before contact with the precipitant.

LEUKOTRIENE MODIFIERS As mentioned earlier, the cysteinyl leukotrienes (LTC4, LTD4, and LTE4) produce many of the critical elements of asthma, and drugs have been developed that either reduce the synthesis of all of the leukotrienes by inhibiting 5-lipoxygenase (5-LO), the enzyme involved in their production, or competitively antagonize the principal moiety (LTD4). Zileuton is the only 5-LO synthesis inhibitor that is available in the United States. It is a modest bronchodilator that reduces asthma morbidity, provides protection against exercise-induced asthma, and diminishes nocturnal symptoms, but it has limited effectiveness against allergens. Hepatic enzyme levels can be elevated after its use, and there are significant interactions with other drugs metabolized in the liver. The LTD4 receptor antagonists (zafirlukast and montelukast) have therapeutic and toxicologic profiles similar to that of zileuton but are long acting and permit twice- to once-daily dose schedules.

This class of drugs does not appear to be uniformly effective in all patients with asthma. Although precise figures are lacking, most authorities put the number of positive responders at 50%. As yet, there is no way of determining prospectively who will benefit, so clinical trials are required. Typically, if there is no improvement after 1 month, treatment can be discontinued. The leukotriene blockers have been associated with uncovering of Churg-Strauss syndrome (Chap. 306).

Miscellaneous Agents It has been suggested that steroid-dependent patients might benefit from the use of immunosuppressant agents such as methotrexate, gold salts, or colchicine. The effects of these agents on steroid dosage and disease activity are minor, and side effects can be considerable. Opiates, sedatives, and tranquilizers should be absolutely avoided in the acutely ill patient with asthma because the risk of depressing alveolar ventilation is great, and respiratory arrest has been reported to occur shortly after their use. Admittedly, most individuals are anxious and frightened, but experience has shown that they can be calmed equally well by the physician's presence and reassurances. ß-Adrenergic blockers and parasympathetic agonists are contraindicated because they can cause marked deterioration in lung function.

Expectorants and mucolytic agents have enjoyed great vogue in the past, but they do not add significantly to the treatment of the acute or chronic phases of this disease. The use of intravenous fluids in the treatment of acute asthma has also been advocated. There is little evidence that this adjunct hastens recovery. Nonstandard bronchodilators, such as intravenous magnesium sulfate, for the treatment of acute asthma attacks are not yet warranted in clinical practice because of the controversy surrounding their efficacy.

Special Instructions The treatment of patients with asthma who have coexisting conditions such as heart disease or pregnancy does not differ materially from that outlined above. Therapy with inhaled ß2-selective and anti-inflammatory agents is the mainstay. The lowest doses of adrenergics that produce the desired effects should be used.

Framework for Management • EMERGENCY SITUATIONS The most effective treatment for acute episodes of asthma requires a systematic approach based on the aggressive use of sympathomimetic agents and serial objective monitoring of key indices of improvement. Reliance on empiricism and subjective assessment is no longer acceptable. Multiple inhalations of a short-acting sympathomimetic, such as albuterol, are the cornerstone of most regimens. These drugs provide three to four times more relief than does intravenous aminophylline. Anticholinergic drugs are not first-line therapy because of their long lag time to onset (~30 to 40 min) and their relatively modest bronchodilator properties. In emergency situations, ß2-agonists can be given every 20 min by handheld nebulizer for 2 to 3 doses. The optimum cumulative dose of albuterol appears to lie between 5 and 10 mg. It does not matter how the adrenergic agonists are inhaled. Treatment with albuterol administered by jet nebulizer, metered dose inhaler, or dry powder inhaler all provide equal resolution in acute situations when the doses are matched. Continuous nebulization of ß2-agonists has also been employed, but it is unclear if it is materially better than the other forms of treatment. Ipratropium can be added to the regimen in an attempt to speed resolution. The benefits on lung function are small, but the need for admission has decreased in some studies. There are no hard and fast rules as to who should be admitted.

Acute episodes of bronchial asthma are one of the most common respiratory emergencies, and it is essential that the physician recognize which episodes of airway obstruction are life-threatening and which patients demand what level of care. These distinctions can be made readily by assessing selected clinical parameters in combination with measures of expiratory flow and gas exchange. The presence of a paradoxical pulse, use of accessory muscles, and marked hyperinflation of the thorax signify severe airways obstruction, and failure of these signs to remit promptly after aggressive therapy mandates objective monitoring of the patient with measurements of arterial blood gases and PEFR3 or FEV12. Although pulse and respiratory rates are commonly recorded, there is no relationship between these variables and the severity of the obstruction or the outcome of treatment.

Patients with the most impairment typically require the most extensive therapy for resolution. If the PEFR3 or FEV12 is =20% of predicted on presentation and does not double within an hour of receiving the preceding therapy, the patient is likely to require extensive treatment, including glucocorticoids, before the obstruction dissipates. This group represents ~20% of all the patients who present for acute care. They generally require inpatient treatment before becoming asymptomatic. In such patients, if the clinical signs of a paradoxical pulse and accessory muscle use are diminishing and/or the PEFR is increasing, there is no need to change medications or doses, but the patient needs to be followed closely. However, if the PEFR falls by 20% of its previous value or if the magnitude of the pulsus paradoxicus is increasing, serial measures of arterial blood gases are required, as well as a reconsideration of the therapeutic modalities being employed. If the patient has hypocarbia, one can afford to continue the current approaches a while longer. On the other hand, if the PaCO2 is within the normal range or is elevated, the patient should be monitored in an intensive care setting, and therapy should be intensified to reverse or arrest the patient's respiratory failure.

Treatment with 70 to 80% helium (balance oxygen) may be beneficial in patients with severe airway obstruction. This gas mixture reduces airway resistance and improves the effect of aerosolized bronchodilators. This form of treatment should be considered in patients whose airway obstruction and gas exchange are worsening despite aggressive therapy. However, there are no large-scale clinical trials comparing this approach with other forms of treatment. The criteria for intubation and ventilatory support have not been standardized. The decision to use this therapy should be made by physicians with the most experience in caring for severely ill asthmatic patients.

Chronic Treatment The goal of chronic therapy is to achieve a stable, asymptomatic state with the best pulmonary function possible using the least amount of medication. The specific recommmendations from consensus guidelines are to promote a state of health encompassing the following: (1) minimal or absent daytime or nocturnal chronic symptoms, (2) minimal or absent exacerbations, (3) no limitation on activities, (4) no absences from school or work, (5) maintenance of normal or near-normal pulmonary functions, (6) the minimal use of short-acting ß2-agonists ( once per day, 1 canister/month), (7) and minimal or absent adverse effects from medications. A primary step is to educate patients to function as partners in their management. The severity of the illness needs to be assessed and monitored with objective measures of lung function. Asthma triggers should be avoided or controlled, and plans should be made for both chronic management and treatment of exacerbations. Regular follow-up care is mandatory.

A stepwise pharmacologic approach recommended by the National Asthma Education and Prevention Program is presented in Table 236-3. The purpose of this schema is to assist and not replace the clinical decision-making required to meet individual patient needs. In general, the simplest approach works best. Infrequent symptoms (step 1) require only the use of an inhaled sympathomimetic on an "as-needed" basis. When the disease worsens to a persistent state (step 2), as manifested by nocturnal awakenings and daytime symptoms, inhaled steroids, mast cell-stabilizing agents, and/or leukotriene modifiers should be added. Methylxanthines can also be employed. If symptoms do not abate (step 3), the dose of inhaled steroids can be increased. An upper limit has not yet been established, but side effects of glucocorticoid excess begin to appear more frequently when the dose exceeds 2.0 mg/kg per d. Persistent asthma complaints can be treated with low- to medium-dose inhaled glucocorticoids and long-acting inhaled ß2-agonists. Alternative treatments include leukotriene modifiers or sustained-release theophylline. In patients with recurrent or perennial symptoms and unstable lung function (step 4), the preferred treatment is high-dose inhaled glucocorticoids and long-acting inhaled ß2-agonists. If needed, oral glucocorticoids in a single daily dose are added to the regimen. Acute symptoms are treated with short-acting rescue medications such as albuterol alone or in combination with a parasympatholytic.

Once control is reached and sustained for several weeks, a step-down reduction in therapy should be undertaken, beginning with the most toxic drug, to find the minimum amount of medication required to keep the patient well. During this process, the PEFR3 should be monitored and medication adjustments should be based on objective changes in lung function as well as on the patient's symptoms. The recommendations in the step-down mode are that treatment be reviewed every 1 to 6 months. In many instances, shorter periods can be employed. We have found that 2 to 4 weeks are a reasonable period. When a patient's asthma is destabilizing, frequent assessments are required. It is important to gain control as quickly as possible and then step down to the least medication necessary to maintain control. If there are difficulties in achieving this goal, then referral to an asthma specialist should be considered. Prior to increasing treatment, an important component is to review patients' inhaler technique, their adherence to therapeutic recommendations, and environment control.

PROGNOSIS AND CLINICAL COURSE

The mortality rate from asthma is small. The most recent figures for the United States indicate fewer than 6000 deaths per year out of a population of ~10 million patients at risk. Death rates, however, appear to be rising in inner-city areas where there is limited availability of health care. Even so, only 0.09 to 0.25% of admissions to hospital are at risk of an untoward event.

Information on the clinical course of asthma suggests a good prognosis, particularly for those whose disease is mild and develops in childhood. The number of children who still have asthma 7 to 10 years after the initial diagnosis varies from 26 to 78%, averaging 46%; however, the percentage who continue to have severe disease is relatively low (6 to 19%).

Although there are reports of patients with asthma developing irreversible changes in lung function, these individuals frequently have comorbid stimuli such as cigarette smoking that could account for these findings. Even when untreated, individuals with asthma do not continuously move from mild to severe disease with time. Rather, their clinical course is characterized by exacerbations and remissions. Some studies suggest that spontaneous remissions occur in approximately 20% of those who develop the disease as adults, and that ~40% can be expected to experience improvement, with less frequent and severe attacks, as they grow older.


	2. bronchiectasis

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BRONCHIECTASIS - Steven E. Weinberger

DEFINITION

Bronchiectasis is an abnormal and permanent dilatation of bronchi. It may be either focal, involving airways supplying a limited region of pulmonary parenchyma, or diffuse, involving airways in a more widespread distribution. Although this definition is based on pathologic changes in the bronchi, diagnosis is often suggested by the clinical consequences of chronic or recurrent infection in the dilated airways and the associated secretions that pool within these airways.

PATHOLOGY

The bronchial dilatation of bronchiectasis is associated with destructive and inflammatory changes in the walls of medium-sized airways, often at the level of segmental or subsegmental bronchi. The normal structural components of the wall, including cartilage, muscle, and elastic tissue, are destroyed and may be replaced by fibrous tissue. The dilated airways frequently contain pools of thick, purulent material, while more peripheral airways are often occluded by secretions or obliterated and replaced by fibrous tissue. Additional microscopic features include bronchial and peribronchial inflammation and fibrosis, ulceration of the bronchial wall, squamous metaplasia, and mucous gland hyperplasia. The parenchyma normally supplied by the affected airways is abnormal, containing varying combinations of fibrosis, emphysema, bronchopneumonia, and atelectasis. As a result of the inflammation, vascularity of the bronchial wall increases, with associated enlargement of the bronchial arteries and anastomoses between the bronchial and pulmonary arterial circulations.

Three different patterns of bronchiectasis were described by Reid in 1950. In cylindrical bronchiectasis the bronchi appear as uniformly dilated tubes that end abruptly at the point that smaller airways are obstructed by secretions. In varicose bronchiectasis the affected bronchi have an irregular or beaded pattern of dilatation resembling varicose veins. In saccular (cystic) bronchiectasis the bronchi have a ballooned appearance at the periphery, ending in blind sacs without recognizable bronchial structures distal to the sacs.

ETIOLOGY AND PATHOGENESIS

Bronchiectasis is a consequence of inflammation and destruction of the structural components of the bronchial wall. Infection is the usual cause of the inflammation; microorganisms such as Pseudomonas aeruginosa and Haemophilus influenzae produce pigments, proteases, and other toxins that injure the respiratory epithelium and impair mucociliary clearance. The host inflammatory response induces epithelial injury, largely as a result of mediators released from neutrophils. As protection against infection is compromised, the dilated airways become more susceptible to colonization and growth of bacteria. Thus, a reinforcing cycle can result, with inflammation producing airway damage, impaired clearance of microorganisms, and further infection, which then completes the cycle by inciting more inflammation.

Infectious Causes Adenovirus and influenza virus are the main viruses that cause bronchiectasis in association with lower respiratory tract involvement. Virulent bacterial infections, especially with potentially necrotizing organisms such as Staphylococcus aureus, Klebsiella, and anaerobes, remain important causes of bronchiectasis when antibiotic treatment of a pneumonia is not given or is significantly delayed. Bronchiectasis has been reported in patients with HIV infection, perhaps at least partly due to recurrent bacterial infection. Tuberculosis can produce bronchiectasis by a necrotizing effect on pulmonary parenchyma and airways and indirectly as a consequence of airway obstruction from bronchostenosis or extrinsic compression by lymph nodes. Nontuberculous mycobacteria are frequently cultured from patients with bronchiectasis, often as secondary infections or colonizing organisms. However, it has now also been recognized that these organisms, especially those of the Mycobacterium avium complex, can serve as primary pathogens associated with the development and/or progression of bronchiectasis. Mycoplasmal and necrotizing fungal infections are rare causes of bronchiectasis.

Impaired host defense mechanisms are often involved in the predisposition to recurrent infections. The major cause of localized impairment of host defenses is endobronchial obstruction. Bacteria and secretions cannot be cleared adequately from the obstructed airway, which develops recurrent or chronic infection. Slowly growing endobronchial neoplasms such as carcinoid tumors may be associated with bronchiectasis. Foreign-body aspiration is another important cause of endobronchial obstruction, particularly in children. Airway obstruction can also result from bronchostenosis, from impacted secretions, or from extrinsic compression by enlarged lymph nodes.

Generalized impairment of pulmonary defense mechanisms occurs with immunoglobulin deficiency, primary ciliary disorders, or cystic fibrosis. Infections and bronchiectasis are therefore often more diffuse. With panhypogammaglobulinemia, the best described of the immunoglobulin disorders associated with recurrent infection and bronchiectasis, patients often also have a history of sinus or skin infections. Selective deficiency of an IgG subclass, especially IgG2, has also been described in a small number of patients with bronchiectasis.

The primary disorders associated with ciliary dysfunction, termed primary ciliary dyskinesia, are responsible for 5 to 10% of cases of bronchiectasis. Numerous defects are encompassed under this category, including structural abnormalities of the dynein arms, radial spokes, and microtubules. The cilia become dyskinetic; their coordinated, propulsive action is diminished, and bacterial clearance is impaired. The clinical effects include recurrent upper and lower respiratory tract infections, such as sinusitis, otitis media, and bronchiectasis. Because normal sperm motility also depends on proper ciliary function, males are generally infertile (Chap. 325). Approximately half of patients with primary ciliary dyskinesia fall into the subgroup of Kartagener's syndrome, in which situs inversus accompanies bronchiectasis and sinusitis.

In cystic fibrosis (Chap. 241), the tenacious secretions in the bronchi are associated with impaired bacterial clearance, resulting in colonization and recurrent infection with a variety of organisms, particularly mucoid strains of P. aeruginosa but also S. aureus, H. influenzae, Escherichia coli, and Burkholderia cepacia.

Noninfectious Causes Some cases of bronchiectasis are associated with exposure to a toxic substance that incites a severe inflammatory response. Examples include inhalation of a toxic gas such as ammonia or aspiration of acidic gastric contents, though the latter problem is often also complicated by aspiration of bacteria. An immune response in the airway may also trigger inflammation, destructive changes, and bronchial dilatation. This mechanism is presumably important for bronchiectasis with allergic bronchopulmonary aspergillosis (ABPA), which is due at least in part to an immune response to Aspergillus organisms that have colonized the airway (Chap. 237). Bronchiectasis accompanying ABPA often involves proximal airways and is associated with mucoid impaction. Bronchiectasis also occurs rarely in ulcerative colitis, rheumatoid arthritis, and Sjogren's syndrome, but it is not known whether an immune response triggers airway inflammation in these patients.

In a1-antitrypsin deficiency, the usual respiratory complication is the early development of panacinar emphysema, but affected individuals may occasionally have bronchiectasis. In the yellow nail syndrome, which is due to hypoplastic lymphatics, the triad of lymphedema, pleural effusion, and yellow discoloration of the nails is accompanied by bronchiectasis in approximately 40% of patients.

CLINICAL MANIFESTATIONS

Patients typically present with persistent or recurrent cough and purulent sputum production. Hemoptysis occurs in 50 to 70% of cases and can be due to bleeding from friable, inflamed airway mucosa. More significant, even massive bleeding is often a consequence of bleeding from hypertrophied bronchial arteries.

When a specific infectious episode initiates bronchiectasis, patients may describe a severe pneumonia followed by chronic cough and sputum production. Alternatively, patients without a dramatic initiating event often describe the insidious onset of symptoms. In some cases, patients are either asymptomatic or have a nonproductive cough, often associated with "dry" bronchiectasis in an upper lobe. Dyspnea or wheezing generally reflects either widespread bronchiectasis or underlying chronic obstructive pulmonary disease. With exacerbations of infection, the amount of sputum increases, it becomes more purulent and often more bloody, and patients may become febrile. Such episodes may be due solely to exacerbations of the airway infection, but associated parenchymal infiltrates sometimes reflect an adjacent pneumonia.

Physical examination of the chest overlying an area of bronchiectasis is quite variable. Any combination of crackles, rhonchi, and wheezes may be heard, all of which reflect the damaged airways containing significant secretions. As with other types of chronic intrathoracic infection, clubbing may be present. Patients with severe, diffuse disease, particularly those with chronic hypoxemia, may have associated cor pulmonale and right ventricular failure. Amyloidosis can result from chronic infection and inflammation but is now seldom seen.

RADIOGRAPHIC AND LABORATORY FINDINGS

Though the chest radiograph is important in the evaluation of suspected bronchiectasis, the findings are often nonspecific. At one extreme, the radiograph may be normal with mild disease. Alternatively, patients with saccular bronchiectasis may have prominent cystic spaces, either with or without air-liquid levels, corresponding to the dilated airways. These may be difficult to distinguish from enlarged airspaces due to bullous emphysema or from regions of honeycombing in patients with severe interstitial lung disease. Other findings are due to dilated airways with thickened walls, which result from peribronchial inflammation. Because of decreased aeration and atelectasis of the associated pulmonary parenchyma, these dilated airways are often crowded together in parallel. When seen longitudinally, the airways appear as "tram tracks"; when seen in cross-section, they produce "ring shadows." Because the dilated airways may be filled with secretions, the lumen may appear dense rather than radiolucent, producing an opaque tubular or branched tubular structure.

Bronchography, which involves coating the airways with a radiopaque, iodinated lipid dye instilled through a catheter or bronchoscope, can provide excellent visualization of bronchiectatic airways. However, this technique has now been replaced by computed tomography (CT), which also provides an excellent view of dilated airways as seen in cross-sectional images (Fig. 240-1). With the advent of high-resolution CT scanning, in which the images are 1.0 to 1.5 mm thick, the sensitivity for detecting bronchiectasis has improved even further. Other features on high-resolution CT scanning can suggest a specific etiology of the bronchiectasis. For example, bronchiectasis of relatively proximal airways suggests ABPA1, whereas the presence of multiple small pulmonary nodules (nodular bronchiectasis) suggests infection with M. avium complex.

Examination of sputum often reveals an abundance of neutrophils and colonization or infection with a variety of possible organisms. Appropriate staining and culturing of sputum often provide a guide to antibiotic therapy.

Additional evaluation is aimed at diagnosing the cause for the bronchiectasis. When bronchiectasis is focal, fiberoptic bronchoscopy may reveal an underlying endobronchial obstruction. In other cases, upper lobe involvement may be suggestive of either tuberculosis or ABPA1. With more widespread disease, measurement of sweat chloride levels for cystic fibrosis, structural or functional assessment of nasal or bronchial cilia or sperm for primary ciliary dyskinesia, and quantitative assessment of immunoglobulins may explain recurrent airway infection. In an asthmatic person with proximal bronchiectasis or other historical features to suggest ABPA, skin testing, serology, and sputum culture for Aspergillus are helpful in confirming the diagnosis.

Pulmonary function tests may demonstrate airflow obstruction as a consequence of diffuse bronchiectasis or associated chronic obstructive lung disease. Bronchial hyperreactivity, e.g., to methacholine challenge, and some reversibility of the airflow obstruction with inhaled bronchodilators are relatively common.

TREATMENT

Therapy has four major goals: (1) elimination of an identifiable underlying problem; (2) improved clearance of tracheobronchial secretions; (3) control of infection, particularly during acute exacerbations; and (4) reversal of airflow obstruction. Appropriate treatment should be instituted when a treatable cause is found, for example, treatment of hypogammaglobulinemia with immunoglobulin replacement, tuberculosis with antituberculous agents, and ABPA1 with glucocorticoids.

Secretions are typically copious and thick and contribute to the symptoms. A variety of mechanical methods and devices accompanied by appropriate positioning can facilitate drainage in patients with copious secretions. Mucolytic agents to thin secretions and allow better clearance are controversial. Aerosolized recombinant DNase, which decreases viscosity of sputum by breaking down DNA released from neutrophils, has been shown to improve pulmonary function in cystic fibrosis, but similar benefits have not been found with bronchiectasis due to other etiologies.

Antibiotics have an important role in management. For patients with infrequent exacerbations characterized by an increase in quantity and purulence of the sputum, antibiotics are commonly used only during acute episodes. Although choice of an antibiotic may be guided by Gram's stain and culture of sputum, empiric coverage (e.g., with ampicillin, amoxicillin, trimethoprim-sulfamethoxazole, or cefaclor) is often given initially. When P. aeruginosa is present, oral therapy with a quinolone or parenteral therapy with an aminoglycoside or third-generation cephalosporin may be appropriate. In patients with chronic purulent sputum despite short courses of antibiotics, more prolonged courses, e.g., with an oral antibiotic or inhaled aminoglycosides, or intermittent but regular courses of single or rotating antibiotics have been used.

Bronchodilators to improve obstruction and aid clearance of secretions are particularly useful in patients with airway hyperreactivity and reversible airflow obstruction. Although surgical therapy was common in the past, more effective antibiotic and supportive therapy has largely replaced surgery. However, when bronchiectasis is localized and the morbidity is substantial despite adequate medical therapy, surgical resection of the involved region of lung should be considered.

When massive hemoptysis, often originating from the hypertrophied bronchial circulation, does not resolve with conservative therapy, including rest and antibiotics, therapeutic options are either surgical resection or bronchial arterial embolization (Chap. 30). Although resection may be successful if disease is localized, embolization is preferable with widespread disease. In patients with extensive disease, chronic hypoxemia and cor pulmonale may indicate the need for long-term supplemental oxygen. For selected patients who are disabled despite maximal therapy, lung transplantation is a therapeutic option.


	3. COPD

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CHRONIC OBSTRUCTIVE PULMONARY DISEASE - John J. Reilly, Jr., Edwin K. Silverman, Steven D. Shapiro

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) has been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a disease state characterized by airflow limitation that is not fully reversible (.com/). COPD includes emphysema, an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not included within COPD.

COPD1 is the fourth leading cause of death and affects 16 million persons in the United States. COPD is also a disease of increasing public health importance around the world. GOLD2 estimates suggest that COPD will rise from the sixth to the third most common cause of death worldwide by 2020.

RISK FACTORS

Cigarette Smoking By 1964, the Advisory Committee to the Surgeon General of the United States concluded that cigarette smoking was a major risk factor for mortality from chronic bronchitis and emphysema. Subsequent longitudinal studies have shown accelerated decline in the volume of air exhaled within the first second of the forced expiratory maneuver (FEV1) in a dose-response relationship to the intensity of cigarette smoking, which is typically expressed as pack-years (average number of packs of cigarettes smoked per day multiplied by the total number of years of smoking). This dose-response relationship between reduced pulmonary function and cigarette smoking intensity accounts for the higher prevalence rates for COPD1 with increasing age. The historically higher rate of smoking among males is the likely explanation for the higher prevalence of COPD among males; however, the prevalence of COPD among females is increasing as the gender gap in smoking rates has diminished in the past 50 years.

Although the causal relationship between cigarette smoking and the development of COPD1 has been absolutely proven, there is considerable variability in the response to smoking. Although pack-years of cigarette smoking is the most highly significant predictor of FEV1 (Fig. 242-1), only 15% of the variability in FEV1 is explained by pack-years. This finding suggests that additional environmental and/or genetic factors contribute to the impact of smoking on the development of airflow obstruction.

Although cigar and pipe smoking may also be associated with the development of COPD1, the evidence supporting such associations is less compelling, likely related to the lower dose of inhaled tobacco byproducts during cigar and pipe smoking.

Airway Responsiveness and COPD A tendency for increased bronchoconstriction in response to a variety of exogenous stimuli, including methacholine and histamine, is one of the defining features of asthma (Chap. 236). However, many patients with COPD1 also share this feature of airway hyperresponsiveness. The considerable overlap between persons with asthma and those with COPD on airway responsiveness, airflow obstruction, and pulmonary symptoms led to the formulation of the Dutch hypothesis. This suggests that asthma, chronic bronchitis, and emphysema are variations of the same basic disease, which is modulated by environmental and genetic factors to produce these pathologically distinct entities. The alternative British hypothesis contends that asthma and COPD are fundamentally different diseases: Asthma is viewed as largely an allergic phenomenon, while COPD results from smoking-related inflammation and damage. Determination of the validity of the Dutch hypothesis vs. the British hypothesis awaits identification of the genetic predisposing factors for asthma and/or COPD, as well as the interactions between these postulated genetic factors and environmental risk factors.

Longitudinal studies that compared airway responsiveness at the beginning of the study to subsequent decline in pulmonary function have demonstrated that increased airway responsiveness is clearly a significant predictor of subsequent decline in pulmonary function. Thus, airways hyperresponsiveness is a risk factor for COPD.

Respiratory Infections These have been studied as potential risk factors for the development and progression of COPD1 in adults; childhood respiratory infections have also been assessed as potential predisposing factors for the eventual development of COPD. The impact of adult respiratory infections on decline in pulmonary function is controversial, but significant long-term reductions in pulmonary function are not typically seen following an episode of bronchitis or pneumonia. The impact of the effects of childhood respiratory illnesses on the subsequent development of COPD has been difficult to assess due to a lack of adequate longitudinal data. Thus, although respiratory infections are important causes of exacerbations of COPD, the association of both adult and childhood respiratory infections to the development and progression of COPD remains to be proven.

Occupational Exposures Increased respiratory symptoms and airflow obstruction have been suggested as resulting from general exposure to dust at work. Several specific occupational exposures, including coal mining, gold mining, and cotton textile dust, have been suggested as risk factors for chronic airflow obstruction. However, although nonsmokers in these occupations developed some reductions in FEV1, the importance of dust exposure as a risk factor for COPD1, independent of cigarette smoking, is not certain. Among workers exposed to cadmium (a specific chemical fume), FEV1, FEV1/FVC, and DLCO were significantly reduced (FVC, forced vital capacity; DLCO, carbon monoxide diffusing capacity of the lung; Chap. 234), consistent with airflow obstruction and emphysema. Although several specific occupational dusts and fumes are likely risk factors for COPD, the magnitude of these effects appears to be substantially less important than the effect of cigarette smoking.

Ambient Air Pollution Some investigators have reported increased respiratory symptoms in those living in urban compared to rural areas, which may relate to increased pollution in the urban settings. However, the relationship of air pollution to chronic airflow obstruction remains unproven. With high rates of COPD1 reported in nonsmoking women in many developing countries, indoor air pollution, usually associated with cooking, has been suggested as a potential contributor. In most populations, ambient air pollution is a much less important risk factor for COPD than cigarette smoking.

Passive, or Second-Hand, Smoking Exposure Exposure of children to maternal smoking results in significantly reduced lung growth. In utero tobacco smoke exposure also contributes to significant reductions in postnatal pulmonary function. Although passive smoke exposure has been associated with reductions in pulmonary function, the importance of this risk factor in the development of the severe pulmonary function reductions in COPD1 remains uncertain.

GENETIC CONSIDERATIONS

Although cigarette smoking is the major environmental risk factor for the development of COPD1, the development of airflow obstruction in smokers is highly variable. Severe a1 antitrypsin (a1AT) deficiency is a proven genetic risk factor for COPD; there is increasing evidence that other genetic determinants also exist.

a1 ANTITRYPSIN DEFICIENCY Many variants of the protease inhibitor (PI) locus that encodes a1AT3 have been described. The common M allele is associated with normal a1AT levels. The S allele, associated with slightly reduced a1AT levels, and the Z allele, associated with markedly reduced a1AT levels, also occur with frequencies 1% in most Caucasian populations. Rare individuals inherit null alleles, which lead to the absence of any a1AT production through a heterogeneous collection of mutations. Individuals with two Z alleles or one Z and one null allele are referred to as PiZ, which is the most common form of severe a1AT deficiency.

Although only 1 to 2% of COPD1 patients inherit severe a1AT4 deficiency, these patients demonstrate that genetic factors can have a profound influence on the susceptibility for developing COPD. PiZ individuals often develop early-onset COPD, but the ascertainment bias in the published series of PiZ individuals — which have usually included many PiZ subjects who were tested for a1AT deficiency because they had COPD — means that the fraction of PiZ individuals who will develop COPD and the age-of-onset distribution for the development of COPD in PiZ subjects remain unknown. Approximately 1 in 3000 individuals in the United States inherits severe a1AT deficiency, but only a small minority of these individuals have been recognized.

A significant percentage of the variability in pulmonary function among PiZ individuals is explained by cigarette smoking; cigarette smokers with severe a1AT5 deficiency are more likely to develop COPD1 at early ages. However, the development of COPD in PiZ subjects, even among current or ex-smokers, is not absolute. Among PiZ nonsmokers, impressive variability has been noted in the development of airflow obstruction. Other genetic and/or environmental factors likely contribute to this variability.

The clinical laboratory test used most frequently to screen for a1AT6 deficiency is measurement of the immunologic level of a1AT in serum (see "Laboratory Findings," below). Specific treatment in the form of a1AT augmentation therapy is available for severe a1AT deficiency as a weekly intravenous infusion (see "Treatment" below).

The risk of lung disease in heterozygous PiMZ individuals, who have intermediate serum levels of a1AT (~60% of PiMM levels), is controversial. Although previous general population surveys have not typically shown increased rates of airflow obstruction in PiMZ compared to PiMM individuals, case-control studies that compared COPD1 patients to control subjects have usually found an excess of PiMZ genotypes in the COPD patient group. Several recent large population studies have suggested that PiMZ subjects are at slightly increased risk for the development of airflow obstruction, but it remains unclear if all PiMZ subjects are at slightly increased risk for COPD or if a subset of PiMZ subjects are at substantially increased risk for COPD due to other genetic or environmental factors.

OTHER GENETIC RISK FACTORS Studies of pulmonary function measurements performed in general population samples have suggested that genetic factors other than PI7 type influence variation in pulmonary function. Familial aggregation of airflow obstruction within families of COPD1 patients has also been demonstrated.

Association studies have compared the distribution of variants in genes hypothesized to be involved in the development of COPD1 in COPD patients and control subjects. However, the results have been quite inconsistent, and no genetic determinants of COPD other than severe a1AT8 deficiency have been definitively proven. Recent genome scan linkage analyses of early-onset COPD families have found evidence for linkage of spirometric phenotypes to several chromosomal regions, but the specific genetic determinants in those regions have yet to be identified.

NATURAL HISTORY

The effects of cigarette smoking on pulmonary function appear to depend on the intensity of smoking exposure, the timing of smoking exposure during growth, and the baseline lung function of the individual; other environmental factors may have similar effects. Although rare individuals may demonstrate precipitous declines in pulmonary function, most individuals follow a steady trajectory of increasing pulmonary function with growth during childhood and adolescence, followed by a gradual decline with aging. Individuals appear to track in their quartile of pulmonary function based upon environmental and genetic factors that put them on different tracks. The risk of eventual mortality from COPD1 is closely associated with reduced levels of FEV1. A graphic depiction of the natural history of COPD is shown as a function of the influences on tracking curves of FEV1 in Fig. 242-2. Death or disability from COPD can result from a normal rate of decline after a reduced growth phase (curve B), an early initiation of pulmonary function decline after normal growth (curve C), or an accelerated decline after normal growth (curve D). The rate of decline in pulmonary function can be modified by changing environmental exposures (i.e., quitting smoking), with smoking cessation at an earlier age providing a more beneficial effect than smoking cessation after marked reductions in pulmonary function have already developed. Genetic factors likely contribute to the level of pulmonary function achieved during growth and to the rate of decline in response to smoking and potentially to other environmental factors as well.

PATHOPHYSIOLOGY

Persistent reduction in forced expiratory flow rates is the most typical finding in COPD1. Increases in the residual volume and the residual volume/total lung capacity ratio, nonuniform distribution of ventilation, and ventilation-perfusion mismatching also occur.

Airflow Obstruction Airflow limitation, also known as airflow obstruction, is typically determined by spirometry, which involves forced expiratory maneuvers after the subject has inhaled to total lung capacity (Fig. 234-4). Key phenotypes obtained from spirometry include FEV1 and the total volume of air exhaled during the entire spirometric maneuver (FVC9). Patients with airflow obstruction related to COPD1 have a chronically reduced ratio of FEV1/FVC. In contrast to asthma, the reduced FEV1 in COPD seldom shows large responses to inhaled bronchodilators, although improvements up to 15% are common. Asthma patients can also develop chronic (not fully reversible) airflow obstruction. Maximal inspiratory flow can be relatively well preserved in the presence of a markedly reduced FEV1. Airflow during forced exhalation is the result of the balance between the elastic recoil of the lungs promoting flow and the resistance of the airways limiting flow. In normal lungs, as well as in lungs affected by COPD, maximal expiratory flow diminishes as the lungs empty because the lung parenchyma provides progressively less elastic recoil and because the cross-sectional area of the airways falls, raising the resistance to airflow. The decrease in flow coincident with decreased lung volume is readily apparent on the expiratory limb of a flow-volume curve. In the early stages of COPD, the abnormality in airflow is only evident at lung volumes at or below the functional residual capacity (closer to residual volume), appearing as a scooped-out lower part of the descending limb of the flow-volume curve. In more advanced disease the entire curve has decreased expiratory flow compared to normal.

Hyperinflation Lung volumes are also routinely assessed in pulmonary function testing. In COPD1 there is often "air trapping" (increased residual volume and increased ratio of residual volume to total lung capacity) and progressive hyperinflation (increased total lung capacity) late in the disease. Hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow, because as lung volume increases, elastic recoil pressure increases and airways enlarge so that airway resistance decreases. Consequently, hyperinflation helps to compensate for airway obstruction. However, hyperinflation can push the diaphragm into a flattened position with a number of adverse effects. First, by decreasing the zone of apposition between the diaphragm and the abdominal wall, positive abdominal pressure during inspiration is not applied as effectively to the chest wall, hindering rib cage movement and impairing inspiration. Second, because the muscle fibers of the flattened diaphragm are shorter than those of a more normally curved diaphragm they are less capable of generating inspiratory pressures than normal. Third, the flattened diaphragm (with increased radius of curvature, r) must generate greater tension (t) to develop the transpulmonary pressure (p) required to produce tidal breathing. This follows from Laplace's law, p = 2t/r. Also, because the thoracic cage is distended beyond its normal resting volume, during tidal breathing the inspiratory muscles must do work to overcome the resistance of the thoracic cage to further inflation instead of gaining the normal assistance from the chest wall recoiling outward towards its resting volume.

Gas Exchange Although there is considerable variability in the relationships between the FEV1 and other physiologic abnormalities in COPD1, certain generalizations may be made. The PaO2 usually remains near normal until the FEV1 is decreased to ~50% of predicted, and even much lower FEV1's can be associated with a normal PaO2, at least at rest. An elevation of PaCO2 is not expected until the FEV1 is

25% of predicted, and even then may not occur. Pulmonary hypertension severe enough to cause cor pulmonale and right ventricular failure due to COPD occurs only in those individuals who have marked decreases in FEV1 (25% of predicted) together with chronic hypoxemia (PaO2 55 mmHg), although earlier in the course some elevation of pulmonary artery pressure, particularly with exercise, may occur (Chap. 220).

Nonuniform ventilation and ventilation-perfusion mismatching are characteristic of COPD1, reflecting the heterogeneous nature of the disease process within the airways and lung parenchyma. Nitrogen wash-out while breathing 100% oxygen is delayed due to regions that are poorly ventilated, and the profile of the nitrogen wash-out curve is consistent with multiple parenchymal compartments having different wash-out rates due to regional differences in compliance and airway resistance. Ventilation/perfusion mismatching accounts for essentially all of the reduction in PaO2 that occurs in COPD; shunting is minimal. This finding explains the effectiveness of modest elevations of inspired oxygen in treating hypoxemia due to COPD and therefore the need to consider problems other than COPD when hypoxemia is difficult to correct with modest levels of supplemental oxygen in the patient with COPD.

PATHOLOGY

Cigarette smoke exposure may affect the large airways, small airways (2 mm diameter), and alveolar space. Changes in large airways cause cough and sputum, while changes in small airways and alveoli are responsible for physiologic alterations. Emphysema and small airway pathology are both present in most persons with COPD1, and their relative contributions to obstruction vary from one person to another. Small airway obstruction likely contributes more to initial obstruction, with emphysema predominating later in the course.

Large Airway Cigarette smoking often results in mucous gland enlargement and goblet cell hyperplasia. These changes are proportional to cough and mucus production that define chronic bronchitis, but these abnormalities are not related to airflow limitation. Goblet cells not only increase in number but in extent through the bronchial tree. Bronchi also undergo squamous metaplasia, which not only predisposes to carcinogenesis but also disrupts mucociliary clearance. Although not as prominent as in asthma, patients may have smooth-muscle hypertrophy and bronchial hyperreactivity leading to airflow limitation. Neutrophil influx has been associated with purulent sputum of upper respiratory tract infections that hamper patients with COPD1. Independent of its proteolytic activity, neutrophil elastase is among the most potent secretagogues identified.

Small Airways The major site of increased resistance in most individuals with COPD1 is in airways =2 mm diameter. Characteristic cellular changes include goblet cell metaplasia and replacement of surfactant-secreting Clara cells with mucus-secreting and infiltrating mononuclear inflammatory cells. Smooth-muscle hypertrophy may also be present. These abnormalities may cause luminal narrowing by excess mucus, edema, and cellular infiltration. Reduced surfactant may increase surface tension at the air-tissue interface, predisposing to airway narrowing or collapse. Fibrosis in the wall may cause airway narrowing directly or, as in asthma, predispose to hyperreactivity. Respiratory bronchiolitis with mononuclear inflammatory cells collecting in distal airway tissues may cause proteolytic destruction of elastic fibers in the respiratory bronchioles and alveolar ducts where the fibers are concentrated as rings around alveolar entrances. The resulting distortion and narrowing of these structures could be involved in the early airflow obstruction in COPD related to cigarette smoking.

Because small airway patency is maintained by the surrounding lung parenchyma that provides radial traction on bronchioles at points of attachment to alveolar septa, loss of bronchiolar attachments as a result of extracellular matrix destruction may cause airway distortion and narrowing in COPD1. Although the significance of alveolar attachments is not resolved, the concept of decreased alveolar attachments leading to small airway obstruction is appealing because it underscores the mechanistic relationship between loss of elastic recoil and increased resistance to airflow in small airways.

Lung Parenchyma Emphysema is characterized by destruction of gas-exchanging airspaces, i.e., the respiratory bronchioles, alveolar ducts, and alveoli. Their walls become perforated and later obliterated with coalescence of small distinct airspaces into abnormal and much larger airspaces. Macrophages accumulate in respiratory bronchioles of young smokers. Bronchoalveolar lavage fluid from such individuals contains roughly five times as many macrophages as lavage from nonsmokers. In smokers' lavage fluid, macrophages comprise 95% of the total cell count and neutrophils, nearly absent in nonsmokers' lavage, account for 1 to 2% of the cells. T lymphocytes, particularly CD8+ cells, are also increased in the alveolar space of smokers.

Emphysema is classified into distinct pathologic types, the most important types being centriacinar and panacinar. Centriacinar emphysema, the type most frequently associated with cigarette smoking, is characterized by enlarged airspaces found (initially) in association with respiratory bronchioles. Centriacinar emphysema is most prominent in the upper lobes and superior segments of lower lobes and is often quite focal. Panacinar emphysema refers to abnormally large airspaces evenly distributed within and across acinar units. Panacinar emphysema is usually observed in patients with a1AT10 deficiency, which has a predilection for the lower lobes. Distinctions between centriacinar and panacinar emphysema are interesting and may ultimately be shown to have different mechanisms of pathogenesis. However, garden-variety, smoking-related emphysema is usually mixed, particularly in advanced cases, and these pathologic classifications are not helpful in the care of patients with COPD1.

PATHOGENESIS

Airflow limitation, the major physiologic change in COPD1, can result from both small airway obstruction and emphysema, as discussed above. Pathologic findings that can contribute to small airway obstruction are described above, but their relative importance is unknown. Fibrosis surrounding the small airways appears to be a significant contributor. Mechanisms leading to collagen accumulation around the airways in the face of increased collagenase activity remain an enigma. Although seemingly counterintuitive, there are several potential mechanisms whereby a proteinase can predispose to fibrosis including proteolytic activation of transforming growth factor ß, and insulin-like growth factor (IGF) binding protein degradation releasing profibrotic IGF. Largely due to availability of suitable animal models, we know much more about the mechanisms involved in emphysema than in small airway obstruction.

The pathogenesis of emphysema can be dissected into three interrelated events (Fig. 242-3): (1) Chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the terminal airspaces of the lung, (2) these inflammatory cells release elastolytic proteinases that damage the extracellular matrix of the lung, and (3) ineffective repair of elastin and perhaps other extracellular matrix components results in pulmonary emphysema.

Inflammation Synthesis of existing data regarding inflammatory cell responses in human lungs following cigarette smoke exposure suggests the following sequence of events: (1) Macrophages patrol the lower airspace under normal conditions, and (2) cigarette smoke comes into contact with and activates lung epithelial cells and alveolar macrophages, leading to cytokine/chemokine release followed by acute neutrophil recruitment and subacute accumulation of macrophages in the respiratory bronchioles and alveolar spaces. T cells (CD8+ CD4+) and perhaps other inflammatory and immune cells are also recruited. Concomitant cigarette smoke-induced loss of cilia in the airway epithelium predisposes to bacterial infection with neutrophilia. Surprisingly, in end-stage lung disease, long after smoking cessation, there remains an exuberant inflammatory response, suggesting that mechanisms of cigarette smoke-induced inflammation that initiate the disease differ from mechanisms that sustain inflammation after smoking cessation. Thus, multiple interacting inflammatory cell types are present and contribute to disease pathogenesis.

Extracellular Matrix Proteolysis Elastin, the principal component of elastic fibers, is a highly stable component of the extracellular matrix that is critical to the integrity of both the small airways and the lung parenchyma. The elastase:antielastase hypothesis proposed in the mid-1960s states that the balance of elastin-degrading enzymes and their inhibitors determines the susceptibility of the lung to destruction that results in airspace enlargement. Neutrophil elastase is a potent serine proteinase that clearly plays a major role in emphysema with associated a1AT11 deficiency and also contributes to the usual forms of emphysema. The neutrophil also possesses serine proteinase 3 and cathepsin G as well as matrix metalloproteinases (MMPs), neutrophil collagenase (MMP-8), and gelatinase B (MMP-9). The macrophage is becoming recognized as a critical cell, producing several elastolytic MMPs including matrilysin (MMP-7), MMP-9, and macrophage elastase (MMP-12). Macrophages also produce potent cysteine proteinases (cathepsins S, L, and K). Animal models, including gene-targeted mice, suggest that macrophage elastases contribute to cigarette smoke-induced emphysema. Collagen degradation is more complex in that, while there is clearly collagen turnover in COPD1, there is a net increase in collagen deposition, particularly around the small airways.

Cell Death Airspace enlargement with loss of alveolar units obviously requires disappearance of both extracellular matrix and cells. Traditional theories suggest that inflammatory cell proteinases degrade lung extracellular matrix as the primary event, with subsequent loss of cell anchoring leading to apoptosis. Recent studies suggest that endothelial and epithelial cell death could be primary events (presumably with secretion of proteinases to dissolve the matrix). Whether these mechanisms play a role in human COPD1 is unknown; however, it has been shown that there is increased septal cell death associated with reduced lung expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (KDR/Flk-1) in human emphysematous lungs.

Ineffective Repair The ability of the adult lung to repair damaged alveoli appears limited. Whether the process of septation that is responsible for alveogenesis during lung development can be reinitiated is not clear. In animal models, treatment with all-trans retinoic acid results in some repair. Also, lung resection results in compensatory lung growth in the remaining lung in animal models. In addition to restoring cellularity following injury, it appears difficult for an adult to restore completely an appropriate extracellular matrix, particularly functional elastic fibers.

CLINICAL PRESENTATION

History The three most common symptoms in COPD1 are cough, sputum production, and exertional dyspnea. Many patients have such symptoms for months or years before seeking medical attention. Although the development of airflow obstruction is a gradual process, many patients date the onset of their disease to an acute illness or exacerbation. A careful history, however, usually reveals the presence of symptoms prior to the acute exacerbation. The development of exertional dyspnea, often described as increased effort to breathe, heaviness, air hunger, or gasping, can be insidious. It is best elicited by a careful history focused on typical physical activities and how the patient's ability to perform them has changed. Activities involving significant arm work, particularly at or above shoulder level, are particularly difficult for patients with COPD. Conversely, activities that allow the patient to brace the arms and use accessory muscles of respiration are better tolerated. Examples of such activities include pushing a shopping cart, walking on a treadmill, or pushing a wheelchair. As COPD advances, the principal feature is worsening dyspnea on exertion with increasing intrusion on the ability to perform vocational or avocational activities. In the most advanced stages, patients are breathless doing simple activities of daily living.

Accompanying worsening airflow obstruction is an increased frequency of exacerbations (described below). Patients may also develop resting hypoxemia and require institution of supplemental oxygen.

Physical Findings In the early stages of COPD1, patients may have an entirely normal physical examination. Current smokers may have signs of active smoking, including an odor of smoke or nicotine staining of fingernails. In patients with more severe disease, the physical examination is notable for a prolonged expiratory phase and expiratory wheezing. In addition, signs of hyperinflation include a barrel chest and enlarged lung volumes with poor diaphragmatic excursion as assessed by percussion. Patients with severe airflow obstruction may also exhibit use of accessory muscles of respiration, sitting in the characteristic "tripod" position to facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles. Patients may develop cyanosis, visible in the lips and nail beds. Patients with predominant emphysema are classically referred to as "pink puffers," a reference to the lack of cyanosis, the use of accessory muscles, and pursed-lip breathing. Such patients also have a dramatic decrease in breath sounds throughout the chest. Patients with a clinical syndrome of chronic bronchitis are classically labeled "blue bloaters," a reference to fluid retention and more marked cyanosis. Typically patients have elements of each and cannot be simply classified. Advanced disease may be accompanied by systemic wasting, with significant weight loss, bitemporal wasting, and diffuse loss of subcutaneous adipose tissue. This syndrome has been associated with both inadequate oral intake and elevated levels of inflammatory cytokines (TNF-a). Such wasting is an independent poor prognostic factor in COPD. Some patients with advanced disease have paradoxical inward movement of the rib cage with inspiration (Hoover's sign), the result of alteration of the vector of diaphragmatic contraction on the rib cage as a result of chronic hyperinflation.

Signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since the advent of supplemental oxygen to the availability of such therapy, patients with advanced disease would develop elevated jugular venous pressures, a right ventricular heave or third heart sound, hepatic congestion, ascites, and peripheral edema as the right ventricle decompensated as a result of chronic pulmonary hypertension.

Clubbing of the digits is not a sign of COPD1, and its presence should alert the clinician to initiate an investigation for causes of clubbing. In this population, the development of lung cancer is the most likely explanation for newly developed clubbing.

Laboratory Findings The hallmark of COPD1 is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1/FVC12 (Chap. 234). With worsening disease severity, lung volumes may increase, resulting in an increase in total lung capacity, functional residual capacity, and residual volume. In patients with emphysema, the diffusing capacity may be reduced, reflecting the parenchymal destruction characteristic of the disease. The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the GOLD2 disease classification (Table 242-1).

While arterial blood gases and oximetry are not sensitive (discussed above), they may demonstrate resting or exertional hypoxemia. Arterial blood gases provide additional information about alveolar ventilation and acid-base status by measuring arterial PCO2 and pH. The change in pH with PCO2 is 0.08 units/10 mmHg acutely and 0.03 units/10 mmHg in the chronic state. Knowledge of the arterial pH therefore allows the classification of ventilatory failure, defined as PCO2 45 mmHg, into acute or chronic conditions (Chap. 250). The arterial blood gas is an important component of the evaluation of patients presenting with symptoms of an exacerbation. An elevated hematocrit suggests the presence of chronic hypoxemia, as does the presence of signs of right ventricular hypertrophy on electrocardiography.

Radiographic studies may assist in the classification of the type of COPD1. Obvious bullae, paucity of parenchymal markings, or hyperlucency suggest the presence of emphysema. Increased lung volumes and flattening of the diaphragm suggest hyperinflation, but do not provide information about chronicity of the changes. Computed tomography (CT) scan is the current definitive test for establishing the presence or absence of emphysema. From a practical perspective, the CT scan does little to influence therapy of COPD except in those individuals considering surgical therapy for their disease (described below).

In patients presenting at =50 years, those with a strong family history, those with predominant basilar disease or those with a minimal smoking history, the serum level of (a1AT13) should be measured. The definitive diagnosis of a1AT deficiency requires PI7 type determination. This is typically performed by isoelectric focusing of serum, which reflects the genotype at the PI locus for the common alleles and many of the rare PI alleles as well. Molecular genotyping can be performed for the common PI alleles (M, S, and Z).

TREATMENT

Stable Phase COPD Only two interventions, smoking cessation and oxygen therapy in chronically hypoxemic patients, have been demonstrated to influence the natural history of patients with COPD1. All other current therapies are directed at improving symptoms and decreasing the frequency and severity of exacerbations. The institution of these therapies should involve an assessment of symptoms, potential risks, costs, and benefits of therapy. This should be followed by an assessment of response to therapy, and a decision should be made whether or not to continue treatment.

Pharmacotherapy • SMOKING CESSATION (SEE ALSO CHAP. 375) It has been shown that middle-aged smokers who were able to successfully stop smoking experienced a significant improvement in the rate of decline in pulmonary function, returning to annual changes similar to that of nonsmoking patients. Thus, all patients with COPD1 should be strongly urged to quit and educated about the benefits of quitting. An emerging body of evidence demonstrates that combining pharmacotherapy with traditional supportive approaches considerably enhances the chances of successful smoking cessation. There are two principal pharmacologic approaches to the problem: bupropion, originally developed as an antidepressant medication, and nicotine replacement therapy. The latter is available as gum, transdermal patches, inhaler, and nasal spray. Current recommendations from the U.S. Surgeon General are that all smokers considering quitting be offered pharmacotherapy, in the absence of any contraindication to treatment.

BRONCHODILATORS In general, bronchodilators are used for symptomatic benefit in patients with COPD1. The inhaled route is preferred for medication delivery as the incidence of side effects is lower than that seen with the use of parenteral medication delivery.

ANTICHOLINERGIC AGENTS While regular use of ipratopium bromide does not appear to influence the rate of decline of lung function, it has been reported to improve symptoms and produce acute improvement in FEV1. Side effects are minor, and a trial of inhaled anticholinergics is recommended in symptomatic patients with COPD1.

BETA AGONISTS These provide symptomatic benefit. The main side effects are tremor and tachycardia. Long-acting inhaled ß agonists, such as salmeterol, have benefits comparable to ipratopium bromide. Their use is more convenient than short-acting agents. The addition of a ß agonist to inhaled anticholinergic therapy has been demonstrated to provide incremental benefit.

INHALED GLUCOCORTICOIDS Several recent trials have failed to find a beneficial effect for the regular use of inhaled glucocorticoids on the rate of decline of lung function, as assessed by FEV1. Patients studied included those with mild to severe airflow obstruction and current and ex-smokers. Patients with significant acute response to inhaled ß agonists were excluded from these trials. Inhaled glucocorticoids were demonstrated to reduce the frequency of exacerbations by 25 to 30%, but their use has been associated with increased rates of oropharyngeal candidiasis and an increased rate of loss of bone density. A trial of inhaled glucocorticoids should be considered in patients with frequent exacerbations, defined as two or more per year, and in patients who demonstrate a significant amount of acute reversibility in response to inhaled bronchodilators.

PARENTERAL CORTICOSTEROIDS The chronic use of oral glucocorticoids for treatment of COPD1 is not recommended because of an unfavorable benefit/risk ratio. The chronic use of oral glucocorticoids is associated with significant side effects, including osteoporosis, weight gain, cataracts, glucose intolerance, and increased risk of infection. A recent study demonstrated that patients tapered off chronic low-dose prednisone (~10 mg/d) did not experience any adverse effect on the frequency of exacerbations, health-related quality of life, or lung function. On average, patients lost ~4.5 kg (~10 lb) when steroids were withdrawn.

THEOPHYLLINE Theophylline produces modest improvements in expiratory flow rates and vital capacity and a slight improvement in arterial oxygen and carbon dioxide levels in patients with moderate to severe COPD1. Nausea is a common side effect; tachycardia and tremor have also been reported.

OXYGEN Supplemental O2 is the only therapy demonstrated to decrease mortality in patients with COPD1. For patients with resting hypoxemia (resting O2 saturation 88% or 90% with signs of pulmonary hypertension or right heart failure), the use of O2 has been demonstrated to have a significant impact on mortality. The Medical Research Council Trial demonstrated that 12 h per day was superior to no O2 supplementation. The Nocturnal Oxygen Therapy Trial demonstrated that O2 use 19 h per day was superior to 12 h per day. Various delivery systems are available, including portable systems that patients may carry to allow mobility outside the home.

Supplemental O2 is commonly prescribed for patients with exertional hypoxemia or nocturnal hypoxemia. Although the rationale for supplemental O2 in these settings is physiologically sound, the benefits of such therapy are not well substantiated.

OTHER AGENTS N-acetyl cysteine has been used in patients with COPD1 for both its mucolytic and antioxidant properties. The latter aspect of its use is the subject of ongoing clinical trials. Specific treatment in the form of intravenous a1AT14 augmentation therapy is available for individuals with severe a1AT deficiency. Despite heat treatment of this product and the absence of reported cases of viral infection from therapy, hepatitis B vaccination is recommended prior to starting augmentation therapy. Although biochemical efficacy of a1AT augmentation therapy has been shown, a randomized controlled trial of a1AT augmentation therapy has never proven the efficacy of augmentation therapy in reducing decline of pulmonary function. Eligibility for a1AT augmentation therapy requires a serum a1AT level 11 u M. Typically, PiZ individuals will qualify, although other rare types associated with severe deficiency (e.g., null-null) are also eligible. Since only a fraction of individuals with severe a1AT deficiency will develop COPD, a1AT augmentation therapy is not recommended for severely a1AT-deficient persons with normal pulmonary function and a normal chest CT15 scan.

Nonpharmacologic Therapies • GENERAL MEDICAL CARE Patients with COPD1 should receive the influenza vaccine annually. Polyvalent pneumococcal vaccine is also recommended, although proof of efficacy in this patient population is not definitive.

PULMONARY REHABILITATION This refers to a treatment program that incorporates education and cardiovascular conditioning. In COPD1, pulmonary rehabilitation has been demonstrated to improve health-related quality of life, dyspnea, and exercise capacity. It has also been shown to reduce rates of hospitalization over a 6- to 12-month period.

LUNG VOLUME REDUCTION SURGERY (LVRS) Surgery to reduce the volume of lung in patients with emphysema was first introduced with minimal success in the 1950s and was reintroduced in the 1990s. It has been reported to produce symptomatic and functional benefit in selected patients, particularly those with emphysema, which is predominant in the upper lobes. The operation may be performed via either a median sternotomy or a thoracoscopic approach. Patients are excluded if they have significant pleural disease (a pulmonary artery systolic pressure 45 mmHg), extreme deconditioning, congestive heart failure, or other severe comorbid conditions. Recent data demonstrate that patients with an FEV1 20% of predicted and either diffusely distributed emphysema on CT16 scan or DLCO 20% of predicted have an increased mortality after the procedure and thus are not candidates for LVRS.

The National Emphysema Treatment trial demonstrated that LVRS17 offers both a mortality benefit and a symptomatic benefit in certain patients with emphysema. The anatomic distribution of emphysema and postrehabilitation exercise capacity are important prognostic characteristics. Patients with upper lobe-predominant emphysema and a low postrehabilitation exercise capacity are most likely to benefit from LVRS.

LUNG TRANSPLANTATION (SEE ALSO CHAP. 248) COPD1 is the single leading indication for lung transplantation. Current recommendations are that candidates for lung transplantation should be =65 years; have severe disability despite maximal medical therapy; and be free of comorbid conditions such as liver, renal, or cardiac disease. In contrast to LVRS18, the anatomic distribution of emphysema and the presence of pulmonary hypertension are not contraindications to lung transplantation. Unresolved issues concerning lung transplantation and COPD include whether single- or double-lung transplant is the preferred procedure.

Exacerbations of COPD Exacerbations are a prominent feature of the natural history of COPD1. Exacerbations are commonly considered to be episodes of increased dyspnea and cough and change in the amount and character of sputum. They may or may not be accompanied by other signs of illness, including fever, myalgias, and sore throat. Self-reported health-related quality of life correlates with frequency of exacerbations more closely than it does with the degree of airflow obstruction. Economic analyses have shown that 70% of COPD-related health care expenditures go to emergency department visits and hospital care; this translates to $10 billion annually in the United States. The frequency of exacerbations increases as airflow obstruction increases; patients with moderate to severe airflow obstruction [GOLD2 stages III,IV (Table 242-1)] have one to three episodes per year.

The approach to the patient experiencing an exacerbation includes an assessment of the severity of the patient's illness, both acute and chronic components; an attempt to identify the precipitant of the exacerbation; and the institution of therapy.

PRECIPITATING CAUSES AND STRATEGIES TO REDUCE FREQUENCY OF EXACERBATIONS A variety of stimuli may result in the final common pathway of airway inflammation and increased symptoms that are characteristic of COPD1 exacerbations. Bacterial infections play a role in many, but by no means all, episodes. Viral respiratory infections are present in approximately one-third of COPD exacerbations. In a significant minority of instances (20 to 35%), no specific precipitant can be identified.

Despite the frequent implication of bacterial infection, chronic suppressive or "rotating" antibiotics are not beneficial in patients with COPD1. This is in contrast to their apparent efficacy in patients with significant bronchiectasis. In patients with bronchiectasis due to cystic fibrosis, suppressive antibiotics have been shown to reduce frequency of hospital admissions.

The role of anti-inflammatory therapy in reducing exacerbation frequency is less well studied. Chronic oral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids did reduce the frequency of exacerbations by 25 to 30% in large clinical trials. It is important to realize that patients with significant pulmonary function reversibility to inhaled bronchodilators were excluded from these trials. Thus, the use of inhaled glucocorticoids should be considered in patients with frequent exacerbations or those who have an asthmatic component, i.e., significant reversibility on pulmonary function testing or marked symptomatic improvement after inhaled bronchodilators.

PATIENT ASSESSMENT The practitioner should attempt to establish the severity of the exacerbation as well as the severity of preexisting COPD1. The more severe either of these two components, the more likely that the patient will require hospital admission. The history should include quantification of the degree of dyspnea by asking about breathlessness during activities of daily living and typical activities for the patient. The patient should be asked about fever; change in character of sputum; any ill contacts; and associated symptoms such as nausea, vomiting, diarrhea, myalgias, and chills. Inquiring about the frequency and severity of prior exacerbations can provide important information. The physical examination should incorporate an assessment of the degree of distress of the patient. Specific attention should be focused on tachycardia, tachypnea, use of accessory muscles, signs of perioral or peripheral cyanosis, the ability to speak in complete sentences, and the patient's mental status. The chest examination should establish the presence or absence of focal findings, degree of air movement, presence or absence of wheezing, asymmetry in the chest examination (suggesting large airway obstruction or pneumothorax mimicking an exacerbation), and the presence or absence of paradoxical motion of the abdominal wall.

Patients with severe underlying COPD1 who are in moderate or severe distress or those with focal findings should have a chest x-ray. Approximately 25% of x-rays in this clinical situation will be abnormal, with the most frequent findings being pneumonia and congestive heart failure. Patients with advanced COPD, those with a history of hypercarbia, those with mental status changes (confusion, sleepiness), or those in significant distress should have an arterial blood gas measurement. The presence of hypercarbia, defined as a PCO2 45 mmHg, has important implications for treatment (discussed below). In contrast to its utility in the management of exacerbations of asthma, measurement of pulmonary function has not been demonstrated to be helpful in the diagnosis or management of exacerbations of COPD.

There are no definitive guidelines concerning the need for inpatient treatment of exacerbations. Patients with respiratory acidosis and hypercarbia, significant hypoxemia, or severe underlying disease or those whose living situation is not conducive to careful observation and the delivery of prescribed treatment should be admitted to the hospital.

Acute Exacerbations • BRONCHODILATORS Typically, patients are treated with an inhaled ß agonist, often with the addition of an anticholinergic agent. These may be administered separately or together, and the frequency of administration depends on the severity of the exacerbation. Patients are often treated initially with nebulized therapy, as such treatment is often easier to administer in older patients or to those in respiratory distress. It has been shown, however, that conversion to metered-dose inhalers is effective when accompanied by education and training of patients and staff. This approach has significant economic benefits and also allows an easier transition to outpatient care. The addition of methylxanthines (such as theophylline) to this regimen can be considered, although convincing proof of its efficacy is lacking. If added, serum levels should be monitored in an attempt to minimize toxicity.

ANTIBIOTICS Patients with COPD1 are frequently colonized with potential respiratory pathogens and it is often difficult to identify conclusively a specific species of bacteria responsible for a particular clinical event. Bacteria frequently implicated in COPD exacerbations include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In addition, Mycoplasma pneumoniae or Chlamydia pneumoniae are found in 5 to 10% of exacerbations. The choice of antibiotic should be based on local patterns of antibiotic susceptibility of the above pathogens, as well as the patient's clinical condition. Most practitioners treat patients with moderate or severe exacerbations with antibiotics, even in the absence of data implicating a specific pathogen.

GLUCOCORTICOIDS Among patients admitted to hospital, the use of glucocorticoids has been demonstrated to reduce the length of stay, hasten recovery, and reduce the chance of subsequent exacerbation or relapse for a period of up to 6 months. A recent study demonstrated that 2 weeks of glucocorticoid therapy produced benefit indistinguishable from 8 weeks of therapy. The GOLD2 guidelines recommend 30 to 40 mg of oral prednisolone or its equivalent for a period of 10 to 14 days. Hyperglycemia, particularly in patients with preexisting diagnosis of diabetes, is the most frequently reported acute complication of glucocorticoid treatment.

OXYGEN Supplemental O2 should be supplied to keep arterial saturations =90%. Hypoxic respiratory drive plays a small role in patients with COPD1. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial PCO2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia.

MECHANICAL VENTILATORY SUPPORT Recent studies have demonstrated that the initiation of noninvasive positive pressure ventilation (NIPPV) in patients with respiratory failure, defined as PCO2 45 mmHg, results in a significant reduction in mortality, need for intubation, complications of therapy, and hospital length of stay. Contraindications to NIPPV include cardiovascular instability, impaired mental status or inability to cooperate, copious secretions or the inability to clear secretions, craniofacial abnormalities or trauma precluding effective fitting of mask, extreme obesity, or significant burns.

Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress despite initial therapy, life-threatening hypoxemia, severe hypercapnia and/or acidosis, markedly impaired mental status, respiratory arrest, hemodynamic instability, or other complications. The goal of mechanical ventilation is to correct the aforementioned conditions. Factors to consider during mechanical ventilatory support include the need to provide sufficient expiratory time in patients with severe airflow obstruction and the presence of auto-PEEP (positive end-expiratory pressure) which can result in patients having to generate significant respiratory effort to trigger a breath during a demand mode of ventilation. The mortality of patients requiring mechanical ventilatory support is 17 to 30% for that particular hospitalization. For patients aged =65 admitted to the intensive care unit for treatment, the mortality doubles over the next year to 60%, regardless of whether mechanical ventilation was required.


	4. cystic fibrosis

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CYSTIC FIBROSIS - Richard C. Boucher

INTRODUCTION

Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease. The first signs and symptoms typically occur in childhood, but about 7% of patients in the United States are diagnosed as adults. Due to improvements in therapy, 38% of patients are now adults (18 years of age) and 13% are past the age of 30. The median survival is 32 years for males and 29 years for females with CF. Thus, CF is no longer only a pediatric disease, and internists must be prepared to recognize and treat its many complications. This disease is characterized by chronic airways infection that ultimately leads to bronchiectasis and bronchiolectasis, exocrine pancreatic insufficiency and intestinal dysfunction, abnormal sweat gland function, and urogenital dysfunction.

PATHOGENESIS

GENETIC CONSIDERATIONS

CF1 is an autosomal recessive disease resulting from mutations in a gene located on chromosome 7. The prevalence of CF varies with the ethnic origin of a population. CF is detected in approximately 1 in 3000 live births in the Caucasian population of North America and northern Europe, 1 in 17,000 live births of African Americans, and 1 in 90,000 live births of the Asian population of Hawaii. The most common mutation in the CF gene (~70% of CF chromosomes) is a 3-bp deletion that results in an absence of phenylalanine at amino acid position 508 (?F508) of the CF gene protein product, known as the CF transmembrane conductance regulator (CFTR). The large number (1000) of relatively uncommon (2%) mutations identified in the CF gene makes it difficult to use DNA diagnostic technologies for identifying heterozygotes in populations at large, and no simple physiologic measurements allow heterozygote detection.

CFTR PROTEIN

The CFTR2 protein is a single polypeptide chain, containing 1480 amino acids, that appears to function both as a cyclic AMP-regulated Cl- channel and, as its name implies, a regulator of other ion channels. The fully processed form of CFTR is found in the plasma membrane in normal epithelia (Fig. 241-1). Biochemical studies indicate that the ?F508 mutation leads to improper processing and intracellular degradation of the CFTR protein. Thus, absence of CFTR at appropriate cellular sites is often part of the pathophysiology of CF1. However, other mutations in the CF gene produce CFTR proteins that are fully processed but are nonfunctional or only partially functional at the appropriate cellular sites.

EPITHELIAL DYSFUNCTION

The epithelia affected by CF1 exhibit different functions in their native state, i.e., some are volume-absorbing (airways and distal intestinal epithelia), some are salt-absorbing but not volume-absorbing (sweat duct), whereas others are volume-secretory (proximal intestine and pancreas). Given this diverse array of native activities, it should not be surprising that CF produces very different effects on patterns of electrolyte and water transport. However, the unifying concept is that all affected tissues express abnormal ion transport function.

ORGAN-SPECIFIC PATHOPHYSIOLOGY

Lung The diagnostic biophysical hallmark of CF1 is the raised transepithelial electric potential difference detected in airway epithelia. The transepithelial potential difference reflects components of both the rate of active ion transport and the resistance to ion flow of the superficial epithelium. CF airway epithelia exhibit both raised Na+ transport rates and decreased Cl- secretion (Fig. 241-2). The Cl- secretory defect reflects the absence of cyclic AMP-dependent kinase and protein kinase C-regulated Cl- transport that is mediated by the Cl- channel function of CFTR3. An important observation is that there is an "alternative" Ca2+-regulated Cl- channel expressed in airway epithelia. This Cl- channel is different from CFTR and is regulated by intracellular Ca2+ levels. This channel can substitute for CFTR with regard to net Cl- transport and may be a potential therapeutic target.

Raised Na+ absorption is a feature of CF1 airway epithelia. Na+ transport abnormalities in CF are not a widespread feature of the CF epithelial phenotype and appear confined to volume-absorbing epithelia. Recent studies demonstrate that the increased Na+ absorption reflects a second function of CFTR4: it acts as a tonic inhibitor of the epithelial Na+ channel. The molecular mechanism mediating this action of CFTR is still unknown.

Mucus clearance appears to be a primary innate defense mechanism for the airways against infection by inhaled bacteria. Normal airways can vary the rates of active Na+ absorption and Cl- secretion to adjust the volume of liquid (water) on airway surfaces for efficient mucus clearance. The central hypothesis of CF airways pathophysiology is that an abnormally high rate of Na+ absorption and low rate of Cl- secretion reduce the salt and water content of mucus and deplete the volume of the periciliary liquid. Both the thickening of mucus and the depletion of the periciliary liquid lead to adhesion of mucus to the airway surface. Mucus adhesion leads to a failure to clear mucus normally from the airways by either ciliary or airflow-dependent (cough) mechanisms. Recent data from both human cell culture models and CF mice in vivo support this hypothesis.

The infection that characterizes CF1 airways involves the mucus layer rather than epithelial or airway wall invasion. The unique predisposition of CF airways to chronic infection by Staphylococcus aureus and Pseudomonas aeruginosa is consistent with failure to clear mucus, but it has also suggested that as yet undefined abnormalities in airway surface liquid may also contribute to selection of these organisms. Recently, it has been demonstrated that reduced O2 tension in CF mucus before, and particularly after, infection may in part select for these bacteria and be responsible for their phenotype. Thus, both mucus stasis and mucus hypoxia may contribute to the propensity for Pseudomonas to grow in biofilm colonies within mucus plaques adherent to CF airway surfaces.

Gastrointestinal Tract The gastrointestinal effects of CF1 are diverse. In the exocrine pancreas, the absence of the CFTR5 Cl- channel in the apical membrane of pancreatic ductal epithelia limits the function of an apical membrane Cl--HCO3- exchanger to secrete bicarbonate and Na+ (by a passive process) into the duct. The failure to secrete Na+ HCO3- and water leads to retention of enzymes in the pancreas and ultimately destruction of virtually all pancreatic tissue. The CF intestinal epithelium, because of the lack of Cl- and water secretion, fails to flush secreted mucins and other macromolecules from intestinal crypts. The diminished CFTR-mediated secretion of liquid may be exacerbated by excessive absorption of liquid, reflecting abnormalities of CFTR-mediated regulation of Na+ absorption (both mediated by Na+ channels and possibly other Na+ transporters, e.g., Na+-H+ exchangers). Both dysfunctions lead to dessicated intraluminal contents and obstruction of both the small and large intestine. In the hepatobiliary system, defective hepatic ductal salt (Cl-) and water secretion causes retention of biliary secretion, focal biliary cirrhosis, and bile duct proliferation in approximately 25 to 30% of patients with CF. The inability of the CF gallbladder epithelium to secrete salt and water can lead to both chronic cholecystitis and cholelithiasis.

Sweat Gland CF1 patients secrete nearly normal volumes of sweat in the sweat acinus. However, CF patients are not able to absorb NaCl from sweat as it moves through the sweat duct due to the inability to absorb Cl- across the ductal epithelial cells.

CLINICAL FEATURES

Most patients with CF1 present with signs and symptoms of the disease in childhood. Approximately 18% of patients present within the first 24 h of life with gastrointestinal obstruction, termed meconium ileus. Other common presentations within the first year or two of life include respiratory tract symptoms, most prominently cough and/or recurrent pulmonary infiltrates, and failure to thrive. A significant proportion of patients (~7%), however, are diagnosed after age 18.

RESPIRATORY TRACT

Upper respiratory tract disease is almost universal in patients with CF1. Chronic sinusitis is common in childhood and leads to nasal obstruction and rhinorrhea. The occurrence of nasal polyps approaches 25% and often requires surgery.

In the lower respiratory tract, the first symptom of CF1 is cough. With time, the cough becomes persistent and produces viscous, purulent, often greenish-colored sputum. Inevitably, periods of clinical stability are interrupted by "exacerbations," defined by increased cough, weight loss, increased sputum volume, and decrements in pulmonary function. These exacerbations require aggressive therapy, including frequent postural drainage and oral antibiotics, and often intravenous antibiotics (see below), with the goal being recovery of lung function. Over the course of years, the exacerbations become more frequent and the recovery of lost lung function incomplete, leading to respiratory failure.

CF1 patients exhibit a characteristic sputum microbiology. Haemophilus influenzae and S. aureus are often the first organisms recovered from samples of lung secretions in newly diagnosed patients with CF. P. aeruginosa is typically cultured from lower respiratory tract secretions thereafter. After repetitive antibiotic exposure, P. aeruginosa, often in a mucoid form, is usually the predominant organism recovered from sputum and may be present as several strains with different antibiotic sensitivities. Burkholderia (formerly Pseudomonas) cepacia has been recovered from CF sputum and is also pathogenic. Patient-to-patient spread of certain strains of this organism indicates that strict infection control in the hospital should be practiced. Other gram-negative rods recovered from CF sputum include Xanthomonas xylosoxidans and B. gladioli, and occasionally mucoid forms of Proteus, Escherichia coli, and Klebsiella. Up to 50% of CF patients have Aspergillus fumigatus in their sputum, and up to 10% of these patients exhibit the syndrome of allergic bronchopulmonary aspergillosis. Mycobacterium tuberculosis is rare in patients with CF. However, 10 to 20% of adult patients with CF have sputum cultures positive for nontuberculous mycobacteria, and in some patients these microorganisms are associated with disease.

The first lung function abnormalities observed in CF1 children, increased ratios of residual volume to total lung capacity, suggest that small airways disease is the first functional lung abnormality in CF. As the disease progresses, both reversible and irreversible changes in forced vital capacity and forced expiratory volume in 1 s are noted. The reversible component reflects the accumulation of intraluminal secretions and/or airway reactivity, which occurs in 40 to 60% of patients with CF. The irreversible component reflects chronic destruction of the airway wall and bronchiolitis.

The earliest chest x-ray change in CF1 lungs is hyperinflation, reflecting small airways obstruction. Later, signs of luminal mucus impaction, bronchial cuffing, and finally bronchiectasis, e.g., ring shadows, are noted. For reasons that are still unknown, the right upper lobe displays the earliest and most severe changes.

CF1 pulmonary disease is associated with many intermittent complications. Pneumothorax is common (10% of patients). The production of small amounts of blood in sputum is common in CF patients with advanced pulmonary disease and appears to be associated with lung infection. Massive hemoptysis is life-threatening and difficult to localize bronchoscopically. With advanced lung disease, digital clubbing becomes evident in virtually all patients with CF. As late events, respiratory failure and cor pulmonale are prominent features of CF.

GASTROINTESTINAL TRACT

The syndrome of meconium ileus in infants presents with abdominal distention, failure to pass stool, and emesis. The abdominal flat plate can be diagnostic, with small-intestinal air-fluid levels, a granular appearance representing meconium, and a small colon. In children and young adults, a syndrome termed meconium ileus equivalent or distal intestinal obstruction syndrome occurs. The syndrome presents with right lower quadrant pain, loss of appetite, occasionally emesis, and often a palpable mass. The syndrome can be confused with appendicitis, which occurs frequently in CF1 patients. The characteristic intestinal abnormalities are complicated by exocrine pancreatic insufficiency in 90% of patients with CF. Insufficient pancreatic enzyme release yields the typical pattern of protein and fat malabsorption, with frequent, bulky, foul-smelling stools. Signs and symptoms of malabsorption of fat-soluble vitamins, including vitamins E and K, are also noted. Pancreatic beta cells are typically spared, but function decreases with age, causing hyperglycemia and increasing requirements for insulin in older patients with CF.

GENITOURINARY SYSTEM

Late onset of puberty is common in both males and females with CF1. The delayed maturational pattern is likely secondary to the effects of chronic lung disease and inadequate nutrition on reproductive endocrine function. More than 95% of male patients with CF are azoospermic, reflecting obliteration of the vas deferens that is probably a result of defective liquid secretion. Some 20% of CF women are infertile due to effects of chronic lung disease on the menstrual cycle; thick, tenacious cervical mucus that blocks sperm migration; and possibly fallopian tube/uterine wall abnormalities in liquid transport. More than 90% of completed pregnancies produce viable infants, and women with CF are generally able to breast-feed infants normally.

DIAGNOSIS

Because of the large number of CF1 mutations, DNA analysis is not used for primary diagnosis. The diagnosis of CF rests on a combination of clinical criteria and analyses of sweat Cl- values. The values for the Na+ and Cl- concentration in sweat vary with age, but typically in adults a Cl- concentration of 70 meq/L discriminates between patients with CF and patients with other lung diseases.

DNA analyses are being performed increasingly in patients with CF1. Comprehensive genotype-phenotype relationships have not yet been established sufficiently for prognosis. A relationship between ?F508 homozygosity and pancreatic insufficiency has been established, but no predictive relationship holds for ?F508 homozygosity and lung disease.

Between 1 and 2% of patients with the clinical syndrome of CF1 have normal sweat Cl- values. In most of these patients, the nasal transepithelial potential difference is raised into the diagnostic range for CF, and sweat acini do not secrete in response to injected ß-adrenergic agonists. A single mutation of the CFTR6 gene, 3849 + 10 kb C?T, is associated with approximately 50% of CF patients with normal sweat Cl- values.

TREATMENT

The major objectives of therapy for CF1 are to promote clearance of secretions and control infection in the lung, provide adequate nutrition, and prevent intestinal obstruction. Ultimately, gene therapy or therapies that restore the processing of misfolded CFTR may be the treatments of choice.

Lung Disease The principal techniques for clearing pulmonary secretions are breathing exercises, flutter valves, and chest percussion. Regular use of these maneuvers is effective in preserving lung function. There is increasing interest in the use of hypertonic saline (3 to 7%) aerosols to augment the clearance of secretions.

More than 95% of CF1 patients die of complications resulting from lung infection. Antibiotics are the principal agents available for treating lung infection, and their use should be guided by sputum culture results. Early intervention with antibiotics is useful, and long courses of treatment are the rule. Because of increased total-body clearance and volume of distribution of antibiotics in CF patients, the required doses are higher for patients with CF than for patients with similar chest infections who do not have CF.

Increased cough and mucus production are treated with antibiotics given orally. Typical oral agents used to treat Staphylococcus include a semisynthetic penicillin or a cephalosporin. Oral ciprofloxacin may reduce pseudomonal bacterial counts and control symptoms. However, its clinical usefulness may be limited by rapid emergence of resistant organisms, and, accordingly, courses should be intermittent (2 to 3 weeks) and not chronic. More severe exacerbations, or exacerbations associated with bacteria resistant to oral antibiotics, require intravenous antibiotics. Traditionally, intravenous therapy has been given in the hospital, but outpatient intravenous antibiotic administration has gained widespread acceptance. Usually, two drugs with different mechanisms of action (e.g., a cephalosporin and an aminoglycoside) are used to treat P. aeruginosa to hinder emergence of resistant organisms. Drug dosage should be monitored so that levels for gentamicin or tobramycin peak at ranges of ~10 ug/mL and exhibit troughs of 2 ug/mL. Cephalosporins (e.g., ceftazidime) and penicillin derivatives also require higher doses. Antibiotics directed at Staphylococcus and/or H. influenzae are added, depending on the results of the culture. Aerosolized antibiotics also have an important role in treating CF1 lung infection. Large doses of aminoglycosides, e.g., 300 mg tobramycin twice daily, via aerosol are effective at delaying exacerbations. Aerosol administration also permits other drugs, e.g., colistin, to be utilized that are relatively ineffective by the intravenous route.

A number of pharmacologic agents for increasing mucus clearance are in use. N-acetylcysteine, which solubilizes mucous glycoproteins, has not been shown to have clinically significant effects on mucus clearance and/or lung function. Recombinant human DNAse, however, degrades the concentrated DNA in CF1 sputum, decreases sputum viscosity, and increases airflow during short-term administration. Long-term (6 months) DNAse treatment increases the time between pulmonary exacerbations. Most patients receive a therapeutic trial of DNAse to test for efficacy, and a sizeable minority demonstrate persistent objective benefits. Clinical trials of experimental drugs aimed at restoring salt and water content of secretions are underway. However, these drugs are not yet available clinically.

Inhaled ß-adrenergic agonists can be useful to control airways constriction. They achieve a short-term increase in airflow, but long-term benefit has not been shown. Inhaled anticholinergics provide an alternative. Oral glucocorticoids may reduce airways inflammation, but their long-term use has been limited by adverse side effects; however, they may be useful for treating allergic bronchopulmonary aspergillosis.

The chronic damage to airway walls reflects to some extent the destructive activities of inflammatory enzymes generated in part by inflammatory cells. To date, specific therapies with antiproteases have not been successfully developed. However, a subset of adolescents with CF1 appear to benefit from long-term, high dose nonsteroidal (ibuprofen) therapy.

A number of pulmonary complications require acute interventions. Atelectasis is best treated with chest physiotherapy and antibiotic therapy. Pneumothoraces involving =10% of the lung can be observed without intervention. The use of chest tubes to expand collapsed, diseased lung often requires long periods of time, and sclerosing agents should be used with caution because of possible limitations for subsequent lung transplantation. Small-volume hemoptysis requires no specific therapy other than treatment of lung infection and assessment of coagulation and vitamin K status. If massive hemoptysis occurs, bronchial artery embolization can be successful. The most ominous complications of CF1 are respiratory failure and cor pulmonale. The most effective conventional therapy for these conditions is vigorous medical management of the lung disease and O2 supplementation. Ultimately, the only effective treatment for respiratory failure in CF is lung transplantation (Chap. 248). The 2-year survival for lung transplantation exceeds 60%, and deaths in transplant patients result principally from graft rejection, often involving obliterative bronchiolitis. The transplanted lungs do not develop a CF-specific phenotype.

Gastrointestinal Disease Maintenance of adequate nutrition is critical for the health of the patient with CF1. Most (90%) of CF patients benefit from pancreatic enzyme replacement. Capsules generally contain between 4000 and 20,000 units of lipase. The dose of enzymes (typically no more than 2500 units/kg per meal) should be adjusted on the basis of weight gain, abdominal symptomatology, and character of stools. Replacement of fat-soluble vitamins, particularly vitamins E and K, is usually required. Hyperglycemia most often becomes manifest in the adult and typically requires insulin treatment.

For treatment of acute obstruction due to distal intestinal obstruction syndrome, megalodiatrizoate or other hypertonic radiocontrast materials delivered by enema to the terminal ileum are utilized. For control of symptoms, adjustment of pancreatic enzymes and the supplementation of intake by salt solutions containing osmotically active agents, e.g., propyleneglycol, are utilized. Persistent symptoms may indicate a diagnosis of gastrointestinal malignancy, which is increased in incidence in patients with CF1. Hepatic and gallbladder complications are treated as for patients without CF. End-stage liver disease can be treated by transplantation, which has a 2-year survival rate 50%.

Psychosocial Factors CF1 imposes a tremendous burden on patients. Health insurance, career options, family planning, and life expectancy become major issues. Thus, assisting patients with the psychosocial adjustments required by CF is critical.


	5. ILDs

Disclaimer: Not mine.. no money made.. don't sue me..

INTERSTITIAL LUNG DISEASES - Talmadge E. King, Jr.

INTRODUCTION

The interstitial lung diseases (ILDs) represent a large number of conditions that involve the parenchyma of the lung — the alveoli, the alveolar epithelium, the capillary endothelium, and the spaces between these structures, as well as the perivascular and lymphatic tissues. This heterogeneous group of disorders is classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders are often associated with considerable morbidity and mortality, and there is little consensus regarding the best management of most of them.

ILDs1 have been difficult to classify because more than 200 known individual diseases are characterized by diffuse parenchymal lung involvement, either as the primary condition or as a significant part of a multiorgan process, as may occur in the connective tissue diseases (CTDs). One useful approach to classification is to separate the ILDs into two groups based on the major underlying histopathology: (1) those associated with predominant inflammation and fibrosis, and (2) those with a predominantly granulomatous reaction in interstitial or vascular areas (Table 243-1). Each of these groups can be further subdivided according to whether the cause is known or unknown. For each ILD there may be an acute phase, and there is usually a chronic one as well. Rarely, some are recurrent, with intervals of subclinical disease.

Sarcoidosis (Chap. 309), idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs2 (Chaps. 300, 301, 302, 303, 304, 305, and 306) are the most common ILDs1 of unknown etiology. Among the ILDs of known cause, the largest group comprises occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Chaps. 237 and 238). A clinical diagnosis is possible for many forms of ILD, especially if an occupational and environmental history is aggressively pursued. For other forms, tissue examination, usually obtained by thoracoscopic or open-lung biopsy, is critical to confirmation of the diagnosis. High-resolution computed tomography (HRCT) scanning promises to improve diagnostic accuracy further as histologic-image correlation is perfected.

PATHOGENESIS

The ILDs1 are nonmalignant disorders and are not caused by identified infectious agents. The precise pathway(s) leading from injury to fibrosis is not known. Although there are multiple initiating agent(s) of injury, the immunopathogenic responses of lung tissue are limited, and the mechanisms of repair have common features. As mentioned above, the two major histopathologic patterns are a granulomatous pattern and a pattern in which inflammation and fibrosis predominate.

GRANULOMATOUS LUNG DISEASE

This process is characterized by an accumulation of T lymphocytes, macrophages, and epithelioid cells organized into discrete structures (granulomas) in the lung parenchyma. The granulomatous lesions can progress to fibrosis. Many patients with granulomatous lung disease remain free of severe impairment of lung function, or, when symptomatic, they improve after treatment. The main differential diagnosis is between sarcoidosis (Chap. 309) and hypersensitivity pneumonitis (Chap. 237).

INFLAMMATION AND FIBROSIS

The initial insult is an injury to the epithelial surface causing inflammation in the air spaces and alveolar walls. If the disease becomes chronic, inflammation spreads to adjacent portions of the interstitium and vasculature and eventually causes interstitial fibrosis. Important histopathologic patterns found in the ILDs1 include: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, respiratory bronchiolitis, organizing pneumonia [bronchiolitis obliterans with organizing pneumonia (BOOP) pattern], diffuse alveolar damage (acute or organizing), desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. The development of irreversible scarring (fibrosis) of alveolar walls, airways, or vasculature is the most feared outcome in all of these conditions because it is often progressive and leads to significant derangement of ventilatory function and gas exchange.

INITIAL EVALUATION

Patients with ILDs1 come to medical attention mainly because of the onset of progressive exertional dyspnea or a persistent, nonproductive cough. Hemoptysis, wheezing, and chest pain may be present. Often, the identification of interstitial opacities on chest x-ray focuses the diagnostic approach toward one of the ILDs.

HISTORY

Duration of Illness Acute presentation (days to weeks), while unusual, occurs with allergy (drugs, fungi, helminths), acute idiopathic interstitial pneumonia, eosinophilic pneumonia, and hypersensitivity pneumonitis. These conditions may be confused with atypical pneumonias because of diffuse alveolar opacities on chest x-ray. Subacute presentation (weeks to months) may occur in all ILDs1 but is seen especially in sarcoidosis, drug-induced ILDs, the alveolar hemorrhage syndromes, cryptogenic organizing pneumonia (COP), and the acute immunologic pneumonia that complicates systemic lupus erythematosus (SLE) or polymyositis. In most ILDs the symptoms and signs form a chronic presentation (months to years). Examples include IPF3, sarcoidosis, pulmonary Langerhans cell histiocytosis (PLCH) (also known as Langerhans cell granulomatosis, eosinophilic granuloma, or histiocytosis X), pneumoconioses, and CTDs4. Episodic presentations are unusual and include eosinophilic pneumonia, hypersensitivity pneumonitis, COP, vasculitides, pulmonary hemorrhage, and Churg-Strauss syndrome.

Age Most patients with sarcoidosis, ILD1 associated with CTD5, lymphangioleiomyomatosis (LAM), PLCH6, and inherited forms of ILD (familial IPF7, Gaucher's disease, Hermansky-Pudlak syndrome) present between the ages of 20 and 40 years. Most patients with IPF are older than 50 years.

Gender LAM8 and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women. Also, ILD1 in Hermansky-Pudlak syndrome and in the CTDs9 is more common in women; an exception is ILD in rheumatoid arthritis (RA), which is more common in men. Because of occupational exposures, pneumoconioses also occur more frequently in men.

Family History Family associations (with an autosomal dominant pattern) have been identified in tuberous sclerosis and neurofibromatosis. An autosomal recessive pattern of inheritance occurs in Niemann-Pick disease, Gaucher's disease, and the Hermansky-Pudlak syndrome. Familial clustering has been increasingly identified in sarcoidosis. Familial lung fibrosis has been associated with mutations in the surfactant protein C gene and is characterized by several patterns of interstitial pneumonia, including nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and UIP10.

Smoking History Patients with PLCH6, desquamative interstitial pneumonia (DIP), Goodpasture's syndrome, respiratory bronchiolitis, and pulmonary alveolar proteinosis are almost always current or former smokers. Two-thirds to 75% of patients with IPF11 have a history of smoking.

Occupation and Environmental History A strict chronologic listing of the patient's lifelong employment must be sought, including specific duties and known exposures. In hypersensitivity pneumonitis (see Fig. 237-1), respiratory symptoms, fever, chills, and an abnormal chest roentgenogram are often temporally related to a hobby (pigeon breeder's disease) or to the workplace (farmer's lung) (Chap. 237). Symptoms may diminish or disappear after the patient leaves the site of exposure for several days; similarly, symptoms may reappear on returning to the exposure site.

Other Important Past History Parasitic infections may cause pulmonary eosinophilia, and therefore a travel history should be taken in patients with known or suspected ILD1. History of risk factors for HIV infection should be elicited from all patients with ILD because several processes may occur at the time of initial presentation or during the clinical course, e.g., HIV infection, BOOP12, acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonitis, or diffuse alveolar hemorrhage.

RESPIRATORY SYMPTOMS AND SIGNS

Dyspnea is a common and prominent complaint in patients with ILD1, especially the idiopathic interstitial pneumonias, hypersensitivity pneumonitis, COP13, sarcoidosis, eosinophilic pneumonias, and PLCH6. Some patients, especially patients with sarcoidosis, silicosis, PLCH, hypersensitivity pneumonitis, lipoid pneumonia, or lymphangitis carcinomatosis, may have extensive parenchymal lung disease on chest x-ray without significant dyspnea, especially early in the course of the illness. Wheezing is an uncommon manifestation of ILD but has been described in patients with chronic eosinophilic pneumonia, Churg-Strauss syndrome, respiratory bronchiolitis, and sarcoidosis. Clinically significant chest pain is uncommon in most ILDs. However, substernal discomfort is common in sarcoidosis. Sudden worsening of dyspnea, especially if associated with acute chest pain, may indicate a spontaneous pneumothorax, which occurs in PLCH, tuberous sclerosis, LAM14, and neurofibromatosis. Frank hemoptysis and blood-streaked sputum are rarely presenting manifestations of ILD but can be seen in the diffuse alveolar hemorrhage (DAH) syndromes, LAM, tuberous sclerosis, and the granulomatous vasculitides. Fatigue and weight loss are common in all ILDs.

PHYSICAL EXAMINATION

The findings are usually not specific. Most commonly, physical examination reveals tachypnea and bibasilar end-inspiratory dry crackles, which are common in most forms of ILD1 associated with inflammation but are less likely to be heard in the granulomatous lung diseases. Crackles may be present in the absence of radiographic abnormalities on the chest radiograph. Scattered late inspiratory high-pitched rhonchi — so-called inspiratory squeaks — are heard in patients with bronchiolitis. The cardiac examination is usually normal except in the mid or late stages of the disease, when findings of pulmonary hypertension and cor pulmonale may become evident (Chap. 220). Cyanosis and clubbing of the digits occur in some patients with advanced disease.

LABORATORY

Antinuclear antibodies, anti-immunoglobulin antibodies (rheumatoid factors), and circulating immune complexes are identified in some patients, even in the absence of a defined CTD15. A raised LDH is a nonspecific finding common to ILDs1. Elevation of the serum angiotensin-converting enzyme level is common in sarcoidosis. Serum precipitins confirm exposure when hypersensitivity pneumonitis is suspected, although they are not diagnostic of the process. Antineutrophil cytoplasmic or anti-basement membrane antibodies are useful if vasculitis is suspected. The electrocardiogram is usually normal unless pulmonary hypertension is present; then it demonstrates right-axis deviation, right ventricular hypertrophy, or right atrial enlargement or hypertrophy. Echocardiography also reveals right ventricular dilatation and/or hypertrophy in the presence of pulmonary hypertension.

CHEST IMAGING STUDIES

Chest X-ray ILD1 may be first suspected on the basis of an abnormal chest radiograph, which most commonly reveals a bibasilar reticular pattern. A nodular or mixed pattern of alveolar filling and increased reticular markings may also be present (see Fig. 233-1). A subgroup of ILDs exhibit nodular opacities with a predilection for the upper lung zones [sarcoidosis, PLCH6, chronic hypersensitivity pneumonitis, silicosis, berylliosis, RA16 (necrobiotic nodular form), ankylosing spondylitis]. The chest x-ray correlates poorly with the clinical or histopathologic stage of the disease. The radiographic finding of honeycombing correlates with pathologic findings of small cystic spaces and progressive fibrosis; when present, it portends a poor prognosis. In most cases, the chest radiograph is nonspecific and usually does not allow a specific diagnosis.

Computed Tomography HRCT17 is superior to the plain chest x-ray for early detection and confirmation of suspected ILD1 (Fig. 243-1). Also, HRCT allows better assessment of the extent and distribution of disease, and it is especially useful in the investigation of patients with a normal chest radiograph. Coexisting disease is often best recognized on HRCT scanning, e.g., mediastinal adenopathy, carcinoma, or emphysema. In the appropriate clinical setting HRCT may be sufficiently characteristic to preclude the need for lung biopsy in IPF18, sarcoidosis, hypersensitivity pneumonitis, asbestosis, lymphangitic carcinoma, and PLCH6. When a lung biopsy is required, HRCT scanning is useful for determining the most appropriate area from which biopsy samples should be taken.

Radionuclide Scanning Gallium-67 or 99mTc-diethylenetriamene penta-acetate (DTPA) scanning have limited roles in evaluating the inflammatory component of ILD1.

PULMONARY FUNCTION TESTING

Spirometry and Lung Volumes Measurement of lung function is important in assessing the extent of pulmonary involvement in patients with ILD1. Most forms of ILD produce a restrictive defect with reduced total lung capacity (TLC), functional residual capacity, and residual volume (Chap. 234). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are reduced, but these changes are related to the decreased TLC. The FEV1/FVC ratio is usually normal or increased. Lung volumes decrease as lung stiffness worsens with disease progression. A few disorders produce interstitial opacities on chest x-ray and obstructive airflow limitation on lung function testing (uncommon in sarcoidosis and hypersensitivity pneumonitis, while common in tuberous sclerosis and LAM19).

Diffusing Capacity A reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) is a common but nonspecific finding in most ILDs1. This decrease is due, in part, to effacement of the alveolar capillary units but, more importantly, to mismatching of ventilation and perfusion (

/

). Lung regions with reduced compliance due to either fibrosis or cellular infiltration may be poorly ventilated but may still maintain adequate blood flow and the ventilation-perfusion mismatch in these regions acts like true venous admixture. The severity of the reduction in DLCO does not correlate with disease stage.

Arterial Blood Gas The resting arterial blood gas may be normal or reveal hypoxemia (secondary to a mismatching of ventilation to perfusion) and respiratory alkalosis. A normal arterial O2 tension (or saturation by oximetry) at rest does not rule out significant hypoxemia during exercise or sleep. CO2 retention is rare and is usually a manifestation of end-stage disease.

CARDIOPULMONARY EXERCISE TESTING

Because hypoxemia at rest is not always present and because severe exercise-induced hypoxemia may go undetected, it is useful to perform exercise testing with measurement of arterial blood gases to detect abnormalities of gas exchange. Arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise [i.e., a high VD/VT ratio (Chap. 234)], and an excessive increase in respiratory rate with a lower-than-expected recruitment of tidal volume provide useful information about physiologic abnormalities and extent of disease. Serial assessment of resting and exercise gas exchange is an excellent method for following disease activity and responsiveness to treatment, especially in patients with IPF20.

FIBEROPTIC BRONCHOSCOPY AND BRONCHOALVEOLAR LAVAGE (BAL)

In selected diseases (e.g., sarcoidosis, hypersensitivity pneumonitis, DAH21 syndrome, cancer, pulmonary alveolar proteinosis), cellular analysis of BAL fluid may be useful in narrowing the differential diagnostic possibilities among various types of ILD1. The role for BAL in defining the stage of disease and assessment of disease progression or response to therapy remains poorly understood, and the usefulness of BAL in the clinical assessment and management remains to be established.

TISSUE AND CELLULAR EXAMINATION

Lung biopsy is the most effective method for confirming the diagnosis and assessing disease activity. The findings may identify a more treatable process than originally suspected, particularly chronic hypersensitivity pneumonitis, COP22, respiratory bronchiolitis-associated ILD1, or sarcoidosis. Biopsy should be obtained before initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or suffers serious side effects from it.

Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (four to eight biopsy samples) is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture's syndrome, or infection are suspected. If a specific diagnosis is not made by transbronchial biopsy, then surgical lung biopsy by video-assisted thoracic surgery or open thoracotomy is indicated. Adequate-sized biopsies from multiple sites, usually from two lobes, should be obtained. Relative contraindications to lung biopsy include serious cardiovascular disease, honeycombing and other roentgenographic evidence of diffuse end-stage disease, severe pulmonary dysfunction, or other major operative risks, especially in the elderly.

TREATMENT

Although the course of ILD1 is variable, progression is common and often insidious. All treatable possibilities should be carefully considered. Since therapy does not reverse fibrosis, the major goals of treatment are permanent removal of the offending agent, when known, and early identification and aggressive suppression of the acute and chronic inflammatory process, thereby reducing further lung damage.

Hypoxemia (PaO2 55 mmHg) at rest and/or with exercise should be managed by supplemental oxygen. If cor pulmonale develops, diuretic therapy and phlebotomy may occasionally be required (Chap. 220).

DRUG THERAPY Glucocorticoids are the mainstay of therapy for suppression of the alveolitis present in ILD1, but the success rate is low. There have been no placebo-controlled trials of glucocorticoids in ILD, so there is no direct evidence that steroids improve survival in many of the diseases for which they are commonly used. Glucocorticoid therapy is recommended for symptomatic ILD patients with idiopathic interstitial pneumonias, eosinophilic pneumonias, COP23, CTD24, sarcoidosis, acute inorganic dust exposures, acute radiation pneumonitis, DAH25, and drug-induced ILD. In organic dust disease, glucocorticoids are recommended for both the acute and chronic stages.

The optimal dose and proper length of therapy with glucocorticoids in the treatment of most ILDs1 are not known. A common starting dose is prednisone, 0.5 to 1 mg/kg in a once-daily oral dose (based on the patient's lean body weight). This dose is continued for 4 to 12 weeks, at which time the patient is reevaluated. If the patient is stable or improved, the dose is tapered to 0.25 to 0.5 mg/kg and is maintained at this level for an additional 4 to 12 weeks depending on the course. Rapid tapering or a shortened course of glucocorticoid treatment can result in recurrence. If the patient's condition continues to decline while on glucocorticoids, a second agent (see below) is often added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per day.

Cyclophosphamide and azathioprine (1 to 2 mg/kg lean body weight per day), with or without glucocorticoids, have been tried with variable success in IPF26, vasculitis, and other ILDs1. An objective response usually requires at least 8 to 12 weeks to occur. In situations in which these drugs have failed or could not be tolerated, other agents, including methotrexate, colchicine, penicillamine, and cyclosporine, have been tried. However, their role in the treatment of ILDs remains to be determined.

Many cases of ILD1 are chronic and irreversible despite the therapy discussed above, and lung transplantation may then be considered (Chap. 248).

INDIVIDUAL FORMS OF ILD

IDIOPATHIC PULMONARY FIBROSIS

IPF27 is the most common form of idiopathic interstitial pneumonia. Separating IPF from other forms of lung fibrosis is an important step in the evaluation of all patients presenting with ILD1. IPF has a distinctly poor response to therapy and prognosis.

Clinical Manifestations Exertional dyspnea, a nonproductive cough, and inspiratory crackles with or without digital clubbing may be present on physical examination. The HRCT28 lung scans typically show patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing (Fig. 243-1). Atypical findings that should suggest an alternative diagnosis include: extensive ground-glass abnormality, nodular opacities, upper or mid-zone predominance, and prominent hilar or mediastinal lymphadenopathy. Pulmonary function tests often reveal a restrictive pattern, a reduced DLCO, and arterial hypoxemia that is exaggerated or elicited by exercise.

Histologic Findings Confirmation of the presence of the UIP10 pattern on histologic examination is essential to confirm this diagnosis. Transbronchial biopsies are not helpful in making the diagnosis of UIP, and surgical biopsy is usually required. The histologic hallmark and chief diagnostic criterion of UIP is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, foci of proliferating fibroblasts, dense collagen fibrosis, and honeycomb changes. These histologic changes affect the peripheral, subpleural parenchyma most severely. The interstitial inflammation is usually patchy and consists of a lymphoplasmacytic infiltrate in the alveolar septa, associated with hyperplasia of type 2 pneumocytes. The fibrotic zones are composed mainly of dense collagen, although scattered foci of proliferating fibroblasts are a consistent finding. The extent of fibroblastic proliferation is predictive of disease progression. Areas of honeycomb change are composed of cystic fibrotic air spaces that are frequently lined by bronchiolar epithelium and filled with mucin. Smooth-muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. Histopathologic examinations during this accelerated phase show a combination of UIP and diffuse alveolar damage. A UIP-like pattern can also be seen with CTDs29, pneumoconioses (e.g., asbestosis), radiation injury, certain drug-induced lung diseases (e.g., nitrofurantoin), and chronic aspiration. Also, a fibrotic pattern may be found in the chronic stage of several specific disorders such as sarcoidosis, chronic hypersensitivity pneumonitis, organized chronic eosinophilic pneumonia, and PLCH6. Since other histopathologic features are frequently present in these syndromes, the term UIP is used for those patients in whom the lesion is idiopathic and not associated with another condition.

TREATMENT

The clinical course is variable, with a 5-year survival rate of 20 to 40% after diagnosis. Treatment options include glucocorticoids, cytotoxic agents (e.g., azathioprine, cyclophosphamide), and antifibrotic agents (e.g., colchicine, pirfenidone, or interferon gamma-1b), alone or in combination with glucocorticoids. However, there is no firm evidence that any of these treatment approaches improves survival or the quality of life. Because of the poor prognosis in untreated patients, a therapeutic trial may be tried. If therapy is recommended, it should be started at the first identification of clinical or physiologic evidence of impairment of lung function. Lung transplantation should be considered for those patients who experience progressive deterioration despite optimal medical management and who meet the established criteria (Chap. 248).

DESQUAMATIVE INTERSTITIAL PNEUMONIA

DIP30 is a rare but distinct clinical and pathologic entity found exclusively in cigarette smokers. The histologic hallmark is the extensive accumulation of macrophages in intraalveolar spaces with minimal interstitial fibrosis. The peak incidence is in the fourth and fifth decades. Most patients present with dyspnea. Lung function testing shows a restrictive pattern with reduced DLCO and arterial hypoxemia. The chest x-ray and HRCT31 scans usually shows diffuse hazy opacities. Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) and a better response to smoking cessation and systemic glucocorticoids than the more common IPF32. Respiratory bronchiolitis-associated ILD1 is considered to be a subset of DIP and is characterized by the accumulation of macrophages in peribronchical alveoli.

ACUTE INTERSTITIAL PNEUMONIA (HAMMAN-RICH SYNDROME)

AIP33 is a rare, fulminant form of lung injury characterized histologically by diffuse alveolar damage on lung biopsy. Most patients are older than 40 years. AIP is similar in presentation to the acute respiratory distress syndrome (ARDS) (Chap. 251) and probably corresponds to the subset of cases of idiopathic ARDS. The onset is usually abrupt in a previously healthy individual. A prodromal illness, usually lasting 7 to 14 days before presentation, is common. Fever, cough, and dyspnea are frequent manifestations at presentation. Diffuse, bilateral, air-space opacification is present on chest radiograph. HRCT34 scans show bilateral, patchy, symmetric areas of ground-glass attenuation. Bilateral areas of air-space consolidation may also be present. A predominantly subpleural distribution may be seen. The diagnosis of AIP requires the presence of a clinical syndrome of idiopathic ARDS and pathologic confirmation of organizing diffuse alveolar damage. Therefore, lung biopsy is required to confirm the diagnosis. Most patients have moderate to severe hypoxemia and develop respiratory failure. Mechanical ventilation is often required. The mortality rate is high (60%), with most patients dying within 6 months of presentation. Recurrences have been reported. However, those who recover often have substantial improvement in lung function. The main treatment is supportive. It is not clear that glucocorticoid therapy is effective.

NONSPECIFIC INTERSTITIAL PNEUMONIA (NSIP)

This condition defines a subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP10, DIP35, AIP36, and idiopathic BOOP37. NSIP is a subacute restrictive process with a presentation similar to IPF38 but usually at a younger age. It is often associated with a febrile illness and there is a relative lack of clubbing. HRCT39 shows bilateral, subpleural ground-glass opacities, often associated with lower lobe volume loss (Fig. 243-2). Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual. Unlike patients with IPF40 (UIP), the majority of patients with NSIP have a good prognosis with most showing improvement after treatment with glucocorticoids.

ILD1 ASSOCIATED WITH CONNECTIVE TISSUE DISORDERS

Clinical findings suggestive of a CTD41 (musculoskeletal pain, weakness, fatigue, fever, joint pains or swelling, photosensitivity, Raynaud's phenomenon, pleuritis, dry eyes, dry mouth) should be sought in any patient with ILD1. The CTDs may be difficult to rule out since the pulmonary manifestations occasionally precede the more typical systemic manifestations by months or years. The most common form of pulmonary involvement is a chronic interstitial pattern similar to that in patients with IPF42. However, determining the precise nature of lung involvement in most of the CTDs is difficult due to the high incidence of lung involvement caused by disease-associated complications of esophageal dysfunction (predisposing to aspiration and secondary infections), respiratory muscle weakness (atelectasis and secondary infections), complications of therapy (opportunistic infections), and associated malignancies.

Progressive Systemic Sclerosis (PSS) (See also Chap. 303) Clinical evidence of ILD1 is present in about one-half of patients with PSS, and pathologic evidence in three-quarters. Pulmonary function tests show a restrictive pattern and impaired diffusing capacity, often before any clinical or radiographic evidence of lung disease appears. Pulmonary vascular disease alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis is strikingly resistant to current modes of therapy.

Rheumatoid Arthritis (See also Chap. 301) ILD1 associated with RA43 is more common in men. Pulmonary manifestations of RA include pleurisy with or without effusion, ILD in up to 20% of cases, necrobiotic nodules (nonpneumoconiotic intrapulmonary rheumatoid nodules) with or without cavities, Caplan's syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, BOOP44, and upper airway obstruction due to arytenoid arthritis.

Systemic Lupus Erythematosus (See also Chap. 300) Lung disease is a common complication in SLE45. Pleuritis with or without effusion is the most common pulmonary manifestation. Other lung manifestations include the following: atelectasis, diaphragmatic dysfunction with loss of lung volumes, pulmonary vascular disease, pulmonary hemorrhage, uremic pulmonary edema, infectious pneumonia, and BOOP46. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD1 is uncommon. It is important to exclude pulmonary infection. Although pleuropulmonary involvement may not be evident clinically, pulmonary function testing, particularly DLCO, reveals abnormalities in many patients with SLE.

Polymyositis and Dermatomyositis (PM/DM) (See also Chap. 369) ILD1 occurs in ~10% of patients with PM/DM, and the clinical features are similar to those of IPF47. Diffuse reticular or nodular opacities with or without an alveolar component occur radiographically, with a predilection for the lung bases. ILD occurs more commonly in the subgroup of patients with an anti-Jo-1 antibody that is directed to histidyl tRNA synthetase. Weakness of respiratory muscles contributing to aspiration pneumonia may be present. A rapidly progressive illness characterized by diffuse alveolar damage may cause respiratory failure.

Sjogren's Syndrome (See also Chap. 304) General dryness and lack of airways secretion cause the major problems of hoarseness, cough, and bronchitis. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition. Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Glucocorticoids have been used in the management of ILD1 associated with Sjogren's syndrome with some degree of clinical success.

DRUG-INDUCED ILD1

Many classes of drugs have the potential to induce diffuse ILD1, which is manifest most commonly as exertional dyspnea and nonproductive cough. A detailed history of the medications taken by the patient is needed to identify drug-induced disease, including over-the-counter medications, oily nose drops, or petroleum products (mineral oil). In most cases, the pathogenesis is unknown, although a combination of direct toxic effects of the drug (or its metabolite) and indirect inflammatory and immunologic events is likely. The onset of the illness may be abrupt and fulminant, or it may be insidious, extending over weeks to months. The drug may have been taken for several years before a reaction develops (e.g., amiodarone), or the lung disease may occur weeks to years after the drug has been discontinued (e.g., carmustine). The extent and severity of disease are usually dose related. Treatment consists of discontinuation of any possible offending drug and supportive care.

CRYPTOGENIC ORGANIZING PNEUMONIA

Also known as idiopathic BOOP48, COP49 is a clinicopathologic syndrome of unknown etiology. The onset is usually in the fifth and sixth decades. The presentation may be of a flulike illness with cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on examination. Pulmonary function is usually impaired, with a restrictive defect and arterial hypoxemia being most common. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Recurrent and migratory pulmonary opacities are common. HRCT50 shows areas of air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone. Lung biopsy shows granulation tissue within small airways, alveolar ducts, and airspaces, with chronic inflammation in the surrounding alveoli. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.

Foci of organizing pneumonia (i.e., a "BOOP51 pattern") is a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders (e.g., cryptococcosis, Wegener's granulomatosis, lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia). Consequently, the clinician must carefully reevaluate any patient found to have this histopathologic lesion to rule out these possibilities.

EOSINOPHILIC PNEUMONIA SEE CHAP. 237

PULMONARY ALVEOLAR PROTEINOSIS

Although not strictly an ILD1, pulmonary alveolar proteinosis (PAP) resembles and is therefore considered with these conditions. It has been proposed that a defect in macrophage function, more specifically an impaired ability to process surfactant, may play a role in the pathogenesis of PAP. This diffuse disease is characterized by the accumulation of an amorphous, periodic acid-Schiff-positive lipoproteinaceous material in the distal air spaces. There is little or no lung inflammation, and the underlying lung architecture is preserved. Mutant mice lacking the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) have a similar accumulation of surfactant and surfactant apoprotein in the alveolar spaces. Moreover, reconstitution of the respiratory epithelium of GM-CSF knockout mice with the GM-CSF gene completely corrects the alveolar proteinosis. Data from BAL52 studies in patients suggest that PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against GM-CSF. These findings suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance. There are three distinct classes of PAP: acquired (90% of all cases), congenital, and secondary. Congenital PAP is transmitted in an autosomal recessive manner and is caused by homozygosity for a frame shift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing. Secondary PAP is rare among adults and is caused by lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies (almost exclusively of hematopoietic origin) and hematopoietic disorders.

The typical age of presentation is 30 to 50 years, and males predominate. The clinical presentation is usually insidious and manifested by progressive exertional dyspnea, fatigue, weight loss, and low-grade fever. A nonproductive cough is common, but occasionally expectoration of "chunky" gelatinous material may occur. Polycythemia, hypergammaglobulinemia, and increased LDH levels are frequent. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP53. Radiographically, bilateral symmetric alveolar opacities located centrally in mid and lower lung zones result in a "bat-wing" distribution. HRCT54 shows a ground-glass opacification and thickened intralobular structures and interlobular septa. Whole lung lavage(s) through a double-lumen endotracheal tube provides relief to many patients with dyspnea or progressive hypoxemia and also may provide long-term benefit.

PULMONARY LYMPHANGIOLEIOMYOMATOSIS

Pulmonary LAM55 is a rare condition that afflicts premenopausal women and should be suspected in young women with emphysema, recurrent pneumothorax, or chylous pleural effusion. It is often misdiagnosed as asthma or chronic obstructive pulmonary disease. Pathologically, LAM is characterized by the proliferation of atypical pulmonary interstitial smooth muscle and cyst formation. The immature-appearing smooth-muscle cells react with monoclonal antibody HMB45, which recognizes a 100-kDa glycoprotein (gp100) originally found in human melanoma cells. Caucasians are affected much more commonly than members of other racial groups. The disease accelerates during pregnancy and abates after oopherectomy. Common complaints at presentation are dyspnea, cough, and chest pain. Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients; it may be bilateral and necessitate pleurodesis. Meningioma and renal angiomyolipomas (hamartomas), characteristic findings in the genetic disorder tuberous sclerosis, are also common in patients with LAM. Chylothorax, chyloperitonium (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or mixed obstructive-restrictive pattern, and gas exchange is often abnormal. HRCT56 shows thin-walled cysts surrounded by normal lung without zonal predominance. Progression is common, with a median survival of 8 to 10 years from diagnosis. Oophorectomy, progesterone (10 mg/d), and, more recently, tamoxifen and luteinizing hormone-releasing hormone analogues have been used. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.

SYNDROMES OF ILD1 WITH DIFFUSE ALVEOLAR HEMORRHAGE

Injury to arterioles, venules, and the alveolar septal (alveolar wall or interstitial) capillaries can result in hemoptysis secondary to disruption of the alveolar-capillary basement membrane. This results in bleeding into the alveolar spaces, which characterizes DAH57. Pulmonary capillaritis, characterized by a neutrophilic infiltration of the alveolar septae, may lead to necrosis of these structures, loss of capillary structural integrity, and the pouring of red blood cells into the alveolar space. Fibrinoid necrosis of the interstitium and red blood cells within the interstitial space are sometimes seen. Bland pulmonary hemorrhage (i.e., DAH without inflammation of the alveolar structures) may also occur.

The clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of the cases. For patients without hemoptysis, new alveolar opacities, a falling hemoglobin level, and hemorrhagic BAL58 fluid point to the diagnosis. The chest radiograph is nonspecific and most commonly shows new patchy or diffuse alveolar opacities. Recurrent episodes of DAH59 may lead to pulmonary fibrosis, resulting in interstitial opacities on the chest radiograph. An elevated white blood cell count and falling hematocrit are frequent. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, may also be present.

Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. The DLCO may be increased, resulting from the increased hemoglobin within the alveoli compartment. Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in Wegener's granulomatosis, microscopic polyangiitis pauci-immune glomerulonephritis, and isolated pulmonary capillaritis. A granular pattern is found in the CTDs60, particularly SLE61, and a characteristic linear deposition is found in Goodpasture's syndrome. Granular deposition of IgA-containing immune complexes is present in Henoch-Schonlein purpura.

The mainstay of therapy for the DAH62 associated with systemic vasculitis, CTD63, Goodpasture's syndrome, and isolated pulmonary capillaritis is intravenous methylprednisolone, 0.5 to 2.0 g daily in divided doses for up to 5 days, followed by a gradual tapering, and then maintenance on an oral preparation. Prompt initiation of therapy is important, particularly in the face of renal insufficiency, since early initiation of therapy has the best chance of preserving renal function. The decision to start other immunosuppressive therapy (cyclophosphamide or azathioprine) acutely depends on the severity of illness.

Goodpasture's Syndrome Pulmonary hemorrhage and glomerulonephritis are features in most patients with this disease. Autoantibodies to renal glomerular and lung alveolar basement membranes are present. This syndrome can present and recur as DAH64 without an associated glomerulonephritis. In such case, circulating anti-basement membrane antibody is often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. The underlying histology may be bland hemorrhage or DAH associated with capillaritis. Plasmapheresis has been recommended as adjunctive treatment.

INHERITED DISORDERS ASSOCIATED WITH ILD

Pulmonary opacities and respiratory symptoms typical of ILD1 can develop in related family members and in several inherited diseases. These include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 358), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher's disease (Chap. 340). The Hermansky-Pudlak syndrome (Chap. 101) is an autosomal recessive disorder in which granulomatous colitis and ILD may occur. It is characterized by oculocutaneous albinism, bleeding diathesis secondary to platelet dysfunction, and the accumulation of a chromolipid, lipofuscin material in cells of the reticuloendothelial system. A UIP10-like pattern is found on lung biopsy, but the alveolar macrophages may contain cytoplasmic ceroid-like inclusions.

ILD WITH A GRANULOMATOUS RESPONSE IN LUNG TISSUE OR VASCULAR STRUCTURES

Inhalation of organic dusts, which cause hypersensitivity pneumonitis, or of inorganic dust, such as silica, which elicits a granulomatous inflammatory reaction leading to ILD1, produces diseases of known etiology (Table 243-1) that are discussed in Chaps. 237 and 238. Sarcoidosis (Chap. 309) is prominent among granulomatous diseases of unknown cause in which ILD is an important feature.

Pulmonary Langerhans Cell Histiocytosis PLCH6 is a rare, smoking-related, diffuse lung disease that primarily affects men between the ages of 20 and 40 years. The clinical presentation varies from an asymptomatic state to a rapidly progressive condition. The most common clinical manifestations at presentation are cough, dyspnea, chest pain, weight loss, and fever. Pneumothorax occurs in about 25% of patients. Hemoptysis and diabetes insipidus are rare manifestations. The radiographic features vary with the stage of the disease. The combination of ill-defined or stellate nodules (2 to 10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH. HRCT65 that reveals a combination of nodules and thin-walled cysts is virtually diagnostic of PLCH. The most frequent pulmonary function abnormality is a markedly reduced DLCO, although varying degrees of restrictive disease, airflow limitation, and diminished exercise capacity may occur. Discontinuance of smoking is the key treatment, resulting in clinical improvement in one-third of patients. Most patients with PLCH suffer persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.

Granulomatous Vasculitides (See also Chap. 306) The granulomatous vasculitides are characterized by pulmonary angiitis (i.e., inflammation and necrosis of blood vessels) with associated granuloma formation (i.e., infiltrates of lymphocytes, plasma cells, epithelioid cells, or histiocytes, with or without the presence of multinucleated giant cells, sometimes with tissue necrosis). The lungs are almost always involved, although any organ system may be affected. Wegener's granulomatosis and allergic angiitis and granulomatosis (Churg-Strauss syndrome) primarily affect the lung but are associated with a systemic vasculitis as well. The granulomatous vasculitides generally limited to the lung include necrotizing sarcoid granulomatosis and benign lymphocytic angiitis and granulomatosis. Granulomatous infection and pulmonary angiitis due to irritating embolic material (e.g., talc) are important known causes of pulmonary vasculitis.

LYMPHOCYTIC INFILTRATIVE DISORDERS

This group of disorders features lymphocyte and plasma cell infiltration of the lung parenchyma. The disorders either are benign or can behave as low-grade lymphomas. Included are angioimmunoblastic lymphadenopathy with dysproteinemia, a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD1 in some cases.

Lymphocytic Interstitial Pneumonitis This rare form of ILD1 occurs in adults, some of whom have an autoimmune disease or dysproteinemia. It has been reported in patients with Sjogren's syndrome and HIV66 infection.

Lymphomatoid Granulomatosis This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis. Although it may affect virtually any organ, it is most frequently characterized by pulmonary, skin, and central nervous system involvement.

BRONCHOCENTRIC GRANULOMATOSIS

Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that describes an uncommon and nonspecific pathologic response to a variety of airway injuries. There is evidence that BG is caused by a hypersensitivity reaction to Aspergillus or other fungi in patients with asthma. About half of the patients described have chronic asthma with severe wheezing and peripheral blood eosinophilia. In patients with asthma, BG probably represents one pathologic manifestation of allergic bronchopulmonary aspergillosis or another allergic mycosis. In patients without asthma, BG has been associated with RA67 and a variety of infections, including tuberculosis, echinococcosis, histoplasmosis, coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with an upper-lobe predominance. Glucocorticoids are the treatment of choice, often with excellent outcome, although recurrences may occur as therapy is tapered or stopped.


	6. pleura and chest

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DISORDERS OF THE PLEURA, MEDIASTINUM, DIAPHRAGM, AND CHEST WALL - Richard W. Light

DISORDERS OF THE PLEURA

PLEURAL EFFUSION

The pleural space lies between the lung and chest wall and normally contains a very thin layer of fluid, which serves as a coupling system. A pleural effusion is present when there is an excess quantity of fluid in the pleural space.

Etiology Pleural fluid accumulates when pleural fluid formation exceeds pleural fluid absorption. Normally, fluid enters the pleural space from the capillaries in the parietal pleura and is removed via the lymphatics situated in the parietal pleura. Fluid can also enter the pleural space from the interstitial spaces of the lung via the visceral pleura or from the peritoneal cavity via small holes in the diaphragm. The lymphatics have the capacity to absorb 20 times more fluid than is normally formed. Accordingly, a pleural effusion may develop when there is excess pleural fluid formation (from the interstitial spaces of the lung, the parietal pleura, or the peritoneal cavity) or when there is decreased fluid removal by the lymphatics.

Diagnostic Approach When a patient is found to have a pleural effusion, an effort should be made to determine the cause (Fig. 245-1). The first step is to determine whether the effusion is a transudate or an exudate. A transudative pleural effusion occurs when systemic factors that influence the formation and absorption of pleural fluid are altered. The leading causes of transudative pleural effusions in the United States are left ventricular failure, pulmonary embolism, and cirrhosis. An exudative pleural effusion occurs when local factors that influence the formation and absorption of pleural fluid are altered. The leading causes of exudative pleural effusions are bacterial pneumonia, malignancy, viral infection, and pulmonary embolism. The primary reason to make this differentiation is that additional diagnostic procedures are indicated with exudative effusions to define the cause of the local disease.

Transudative and exudative pleural effusions are distinguished by measuring the lactate dehydrogenase (LDH) and protein levels in the pleural fluid. Exudative pleural effusions meet at least one of the following criteria, whereas transudative pleural effusions meet none:

1. pleural fluid protein/serum protein 0.5

2. pleural fluid LDH1/serum LDH 0.6

3. pleural fluid LDH more than two-thirds normal upper limit for serum

The above criteria misidentify approximately 25% of transudates as exudates. If one or more of the exudative criteria are met and the patient is clinically thought to have a condition producing a transudative effusion, the difference between the albumin levels in the serum and the pleural fluid should be measured. If this gradient is greater than 12 g/L (1.2 g/dL), the exudative categorization by the above criteria can be ignored because almost all such patients have a transudative pleural effusion.

If a patient has an exudative pleural effusion, the following tests on the pleural fluid should be obtained: description of the fluid, glucose level, differential cell count, microbiologic studies, and cytology.

Effusion due to Heart Failure The most common cause of pleural effusion is left ventricular failure. The effusion occurs because the increased amounts of fluid in the lung interstitial spaces exit in part across the visceral pleura. This overwhelms the capacity of the lymphatics in the parietal pleura to remove fluid. A diagnostic thoracentesis should be performed if the effusions are not bilateral and comparable in size, if the patient is febrile, or if the patient has pleuritic chest pain to verify that the patient has a transudative effusion. Otherwise the patient is best treated with diuretics. If the effusion persists despite diuretic therapy, a diagnostic thoracentesis should be performed.

Hepatic Hydrothorax Pleural effusions occur in approximately 5% of patients with cirrhosis and ascites. The predominant mechanism is the direct movement of peritoneal fluid through small holes in the diaphragm into the pleural space. The effusion is usually right-sided and frequently is large enough to produce severe dyspnea. If medical management does not control the ascites and the effusion, the best treatment is a liver transplant. If the patient is not a candidate for this, the best alternative is insertion of a transjugular intrahepatic portal systemic shunt.

Parapneumonic Effusion Parapneumonic effusions are associated with bacterial pneumonia, lung abscess, or bronchiectasis and are probably the most common exudative pleural effusion in the United States. Empyema refers to a grossly purulent effusion.

Patients with aerobic bacterial pneumonia and pleural effusion present with an acute febrile illness consisting of chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness with weight loss, a brisk leukocytosis, mild anemia, and a history of some factor that predisposes them to aspiration.

The possibility of a parapneumonic effusion should be considered whenever a patient with a bacterial pneumonia is initially evaluated. The presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph, computed tomography (CT) of the chest, or ultrasound. If the free fluid separates the lung from the chest wall by more than 10 mm on one of these examinations, a therapeutic thoracentesis should be performed. Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include:

1. loculated pleural fluid

2. pleural fluid pH 7.20

3. pleural fluid glucose 3.3 mmol/L (60 mg/dL)

4. positive Gram stain or culture of the pleural fluid

5. the presence of gross pus in the pleural space

If the fluid recurs after the initial therapeutic thoracentesis, a repeat thoracentesis should be performed if any of the above characteristics are present. If the fluid recurs a second time, tube thoracostomy should be performed if any of the poor prognostic factors are present. If the fluid cannot be completely removed with the therapeutic thoracentesis, consideration should be given to inserting a chest tube and instilling a thrombolytic (streptokinase, 250,000 units) or performing thoracoscopy with the breakdown of adhesions. Decortication should be considered when the above are ineffective.

Effusion Secondary to Malignancy Malignant pleural effusions secondary to metastatic disease are the second most common type of exudative pleural effusion. The three tumors that cause approximately 75% of all malignant pleural effusions are lung carcinoma, breast carcinoma, and lymphoma. Most patients complain of dyspnea, which is frequently out of proportion to the size of the effusion. The pleural fluid is an exudate, and its glucose level may be reduced if the tumor burden in the pleural space is high. BR

The diagnosis is usually made via cytology of the pleural fluid. If the initial cytologic examination is negative, then thoracoscopy is the best next procedure if malignancy is strongly suspected. At the time of thoracoscopy, a procedure such as pleural abrasion should be performed to effect a pleurodesis. If thoracoscopy is unavailable, then needle biopsy of the pleura should be performed.

Patients with a malignant pleural effusion are treated symptomatically for the most part, since the presence of the effusion indicates disseminated disease and most malignancies associated with pleural effusion are not curable with chemotherapy. The only symptom that can be attributed to the effusion itself is dyspnea. If the patient's lifestyle is compromised by dyspnea, and if the dyspnea is relieved with a therapeutic thoracentesis, then one of the following procedures should be considered: (1) tube thoracostomy with the instillation of a sclerosing agent such as doxycycline, 500 mg; or (2) outpatient insertion of a small indwelling catheter.

Mesothelioma Malignant mesotheliomas are primary tumors that arise from the mesothelial cells that line the pleural cavities. Most are related to asbestos exposure. Patients with mesothelioma present with chest pain and shortness of breath. The chest radiograph reveals a pleural effusion, generalized pleural thickening, and a shrunken hemithorax. Thoracoscopy or open pleural biopsy is usually necessary to establish the diagnosis. Various treatment modalities, including radical surgery, chemotherapy, and radiation therapy, have been tried, but none has been proven to be more effective than symptomatic therapy. It is recommended that chest pain be treated with opiates and that shortness of breath be treated with oxygen and/or opiates.

Effusion Secondary to Pulmonary Embolization The diagnosis most commonly overlooked in the differential diagnosis of a patient with an undiagnosed pleural effusion is pulmonary embolism. Dyspnea is the most common symptom. The pleural fluid is usually exudative but can be transudative. The diagnosis is established by spiral CT2 scan or pulmonary arteriography (Chap. 244). Treatment of the patient with a pleural effusion secondary to pulmonary embolism is the same as for any patient with pulmonary emboli. If the pleural effusion increases in size after anticoagulation, the patient probably has recurrent emboli or another complication such as a hemothorax or a pleural infection.

Tuberculous Pleuritis (See also Chap. 150) In many parts of the world, the most common cause of an exudative pleural effusion is tuberculosis (TB), but this is relatively uncommon in the United States. Tuberculous pleural effusions are thought to be due primarily to a hypersensitivity reaction to tuberculous protein in the pleural space. Patients with tuberculous pleuritis present with fever, weight loss, dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate with predominantly small lymphocytes. The diagnosis is established by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase 45 IU/L, interferon ? 140 pg/mL, or positive polymerase chain reaction (PCR) for tuberculous DNA). Alternatively, the diagnosis can be established by culture of the pleural fluid, needle biopsy of the pleura, or thoracoscopy. The recommended treatment of pleural and pulmonary tuberculosis is identical (Chap. 150).

Effusion Secondary to Viral Infection Viral infections are probably responsible for a sizable percentage of undiagnosed exudative pleural effusions. In many series, no diagnosis is established for approximately 20% of exudative effusions, and these effusions resolve spontaneously with no long-term residua. The importance of these effusions is that one should not be too aggressive in trying to establish a diagnosis for the undiagnosed effusion, particularly if the patient is improving clinically.

AIDS

Pleural effusions are uncommon in such patients. The most common cause is Kaposi's sarcoma, followed by parapneumonic effusion. Other common causes are TB3, cryptococcosis, and primary effusion lymphoma. Pleural effusions are very uncommon with Pneumocystis carinii infection.

Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space. The most common cause of chylothorax is trauma, but it also may result from tumors in the mediastinum. Patients with chylothorax present with dyspnea, and a large pleural effusion is present on the chest radiograph. Thoracentesis reveals milky fluid, and biochemical analysis reveals a triglyceride level that exceeds 1.2 mmol/L (110 mg/dL). Patients with chylothorax and no obvious trauma should have a lymphangiogram and a mediastinal CT4 scan to assess the mediastinum for lymph nodes. The treatment of choice for most chylothoraces is implantation of a pleuroperitoneal shunt. Patients with chylothoraces should not undergo prolonged tube thoracostomy with chest tube drainage because this will lead to malnutrition and immunologic incompetence.

Hemothorax When a diagnostic thoracentesis reveals bloody pleural fluid, a hematocrit should be obtained on the pleural fluid. If the hematocrit is 50% that of the peripheral blood, the patient has a hemothorax. Most hemothoraces are the result of trauma; other causes include rupture of a blood vessel or tumor. Most patients with hemothorax should be treated with tube thoracostomy, which allows continuous quantification of bleeding. If the bleeding emanates from a laceration of the pleura, apposition of the two pleural surfaces is likely to stop the bleeding. If the pleural hemorrhage exceeds 200 mL/h, consideration should be given to thoracotomy.

Miscellaneous Causes of Pleural Effusion There are many other causes of pleural effusion (Table 245-1). Key features of some of these conditions are as follows: If the pleural fluid amylase level is elevated, the diagnosis of esophageal rupture or pancreatic disease is likely. If the patient is febrile, has predominantly polymorphonuclear cells in the pleural fluid, and has no pulmonary parenchymal abnormalities, an intraabdominal abscess should be considered. The diagnosis of an asbestos pleural effusion is one of exclusion. Benign ovarian tumors can produce ascites and a pleural effusion (Meigs' syndrome), as can the ovarian hyperstimulation syndrome. Several drugs can cause pleural effusion; the associated fluid is usually eosinophilic. Pleural effusions commonly occur following coronary artery bypass surgery. Effusions occurring within the first weeks are typically left-sided and bloody, with large numbers of eosinophils, and respond to one or two therapeutic thoracenteses. Effusions occurring after the first few weeks are typically left-sided and clear yellow, with predominantly small lymphocytes, and tend to recur. Other medical manipulations that induce pleural effusions include abdominal surgery, endoscopic variceal sclerotherapy, radiation therapy, liver or lung transplantation, or the intravascular insertion of central lines.

PNEUMOTHORAX

Pneumothorax is the presence of gas in the pleural space. A spontaneous pneumothorax is one that occurs without antecedent trauma to the thorax. A primary spontaneous pneumothorax occurs in the absence of underlying lung disease, while a secondary spontaneous pneumothorax occurs in its presence. A traumatic pneumothorax results from penetrating or nonpenetrating chest injuries. A tension pneumothorax is a pneumothorax in which the pressure in the pleural space is positive throughout the respiratory cycle.

Primary Spontaneous Pneumothorax Primary spontaneous pneumothoraces are usually due to rupture of apical pleural blebs, small cystic spaces that lie within or immediately under the visceral pleura. Primary spontaneous pneumothoraces occur almost exclusively in smokers, which suggests that these patients have subclinical lung disease. Approximately one-half of patients with an initial primary spontaneous pneumothorax will have a recurrence. The initial recommended treatment for primary spontaneous pneumothorax is simple aspiration. If the lung does not expand with aspiration, or if the patient has a recurrent pneumothorax, thoracoscopy with stapling of blebs and pleural abrasion is indicated. Thoracoscopy or thoracotomy with pleural abrasion is almost 100% successful in preventing recurrences.

Secondary Spontaneous Pneumothorax Most secondary spontaneous pneumothoraces are due to chronic obstructive pulmonary disease, but pneumothoraces have been reported with virtually every lung disease. Pneumothorax in patients with lung disease is more life-threatening than it is in normal individuals because of the lack of pulmonary reserve in these patients. Nearly all patients with secondary spontaneous pneumothorax should be treated with tube thoracostomy and the instillation of a sclerosing agent such as doxycycline. Patients with secondary spontaneous pneumothoraces who have a persistent air leak, an unexpanded lung after 3 days of tube thoracostomy, or a recurrent pneumothorax should be subjected to thoracoscopy with bleb resection and pleural abrasion.

Traumatic Pneumothorax Traumatic pneumothoraces can result from both penetrating and nonpenetrating chest trauma. Traumatic pneumothoraces should be treated with tube thoracostomy unless they are very small. If a hemopneumothorax is present, one chest tube should be placed in the superior part of the hemithorax to evacuate the air, and another should be placed in the inferior part of the hemithorax to remove the blood. Iatrogenic pneumothorax is a type of traumatic pneumothorax that is becoming more common. The leading causes are transthoracic needle aspiration, thoracentesis, and the insertion of central intravenous catheters. The treatment differs according to the degree of distress and can be observation, supplemental oxygen, aspiration, or tube thoracostomy.

Tension Pneumothorax This condition usually occurs during mechanical ventilation or resuscitative efforts. The positive pleural pressure is life-threatening both because ventilation is severely compromised and because the positive pressure is transmitted to the mediastinum, which results in decreased venous return to the heart and reduced cardiac output.

Difficulty in ventilation during resuscitation or high peak inspiratory pressures during mechanical ventilation strongly suggests the diagnosis. The diagnosis is made by the finding of an enlarged hemithorax with no breath sounds and shift of the mediastinum to the contralateral side. Tension pneumothorax must be treated as a medical emergency. If the tension in the pleural space is not relieved, the patient is likely to die from inadequate cardiac output or marked hypoxemia. A large-bore needle should be inserted into the pleural space through the second anterior intercostal space. If large amounts of gas escape from the needle after insertion, the diagnosis is confirmed. The needle should be left in place until a thoracostomy tube can be inserted.

DISORDERS OF THE MEDIASTINUM

The mediastinum is the region between the pleural sacs. It is separated into three compartments. The anterior mediastinum extends from the sternum anteriorly to the pericardium and brachiocephalic vessels posteriorly. It contains the thymus gland, the anterior mediastinal lymph nodes, and the internal mammary arteries and veins. The middle mediastinum lies between the anterior and posterior mediastina and contains the heart; the ascending and transverse arches of the aorta; the venae cavae; the brachiocephalic arteries and veins; the phrenic nerves; the trachea, main bronchi, and their contiguous lymph nodes; and the pulmonary arteries and veins. The posterior mediastinum is bounded by the pericardium and trachea anteriorly and the vertebral column posteriorly. It contains the descending thoracic aorta, esophagus, thoracic duct, azygos and hemiazygos veins, and the posterior group of mediastinal lymph nodes.

MEDIASTINAL MASSES

The first step in evaluating a mediastinal mass is to place it in one of the three mediastinal compartments, since each has different characteristic lesions. The most common lesions in the anterior mediastinum are thymomas, lymphomas, teratomatous neoplasms, and thyroid masses. The most common masses in the middle mediastinum are vascular masses, lymph node enlargement from metastases or granulomatous disease, and pleuropericardial and bronchogenic cysts. In the posterior mediastinum, neurogenic tumors, meningoceles, meningomyeloceles, gastroenteric cysts, and esophageal diverticula are commonly found.

CT5 scanning is the most valuable imaging technique for evaluating mediastinal masses and is the only imaging technique that should be done in most instances. Barium studies of the gastrointestinal tract are indicated in many patients with posterior mediastinal lesions, since hernias, diverticula, and achalasia are readily diagnosed in this manner. An 131I nuclear medicine scan can efficiently establish the diagnosis of intrathoracic goiter.

A definite diagnosis can be obtained with mediastinoscopy or anterior mediastinotomy in many patients with masses in the anterior or middle mediastinal compartments. A diagnosis can be established without thoracotomy via percutaneous fine-needle aspiration biopsy or endoscopic ultrasound-guided biopsy of mediastinal masses. In many cases the diagnosis can be established and the mediastinal mass removed with video-assisted thoracoscopy.

ACUTE MEDIASTINITIS

Most cases of acute mediastinitis either are due to esophageal perforation or occur after median sternotomy for cardiac surgery. Patients with esophageal rupture are acutely ill with chest pain and dyspnea due to the mediastinal infection. The esophageal rupture can occur spontaneously or as a complication of esophagoscopy or the insertion of a Blakemore tube. Appropriate treatment is exploration of the mediastinum with primary repair of the esophageal tear and drainage of the pleural space and the mediastinum.

The incidence of mediastinitis following median sternotomy is 0.4 to 5.0%. Patients most commonly present with wound drainage. Other presentations include sepsis or a widened mediastinum. The diagnosis is usually established with mediastinal needle aspiration. Treatment includes immediate drainage, debridement, and parenteral antibiotic therapy, but the mortality still exceeds 20%.

CHRONIC MEDIASTINITIS

The spectrum of chronic mediastinitis ranges from granulomatous inflammation of the lymph nodes in the mediastinum to fibrosing mediastinitis. Most cases are due to TB3 or histoplasmosis, but sarcoidosis, silicosis, and other fungal diseases are at times causative. Patients with granulomatous mediastinitis are usually asymptomatic. Those with fibrosing mediastinitis usually have signs of compression of some mediastinal structure such as the superior vena cava or large airways, phrenic or recurrent laryngeal nerve paralysis, or obstruction of the pulmonary artery or proximal pulmonary veins. Other than antituberculous therapy for tuberculous mediastinitis, no medical or surgical therapy has been demonstrated to be effective for mediastinal fibrosis.

PNEUMOMEDIASTINUM

In this condition, there is gas in the interstices of the mediastinum. The three main causes are: (1) alveolar rupture with dissection of air into the mediastinum; (2) perforation or rupture of the esophagus, trachea, or main bronchi; and (3) dissection of air from the neck or the abdomen into the mediastinum. Typically, there is severe substernal chest pain with or without radiation into the neck and arms. The physical examination usually reveals subcutaneous emphysema in the suprasternal notch and Hamman's sign, which is a crunching or clicking noise synchronous with the heartbeat and best heard in the left lateral decubitus position. The diagnosis is confirmed with the chest radiograph. Usually no treatment is required, but the mediastinal air will be absorbed faster if the patient inspires high concentrations of oxygen. If mediastinal structures are compressed, the compression can be relieved with needle aspiration.

DISORDERS OF THE DIAPHRAGM

DIAPHRAGMATIC PARALYSIS

The presence of bilateral diaphragmatic paralysis almost always causes severe morbidity in adults. The most common causes include high spinal cord injury, thoracic trauma (including cardiac surgery), multiple sclerosis, anterior horn disease, and muscular dystrophy. Most patients with severe diaphragmatic weakness present with hypercapnic respiratory failure, frequently complicated by cor pulmonale and right ventricular failure, atelectasis, and pneumonia.

The degree of diaphragmatic weakness is best quantitated by measuring transdiaphragmatic pressures. The treatment of choice is assisted ventilation for all or part of each day. This is best accomplished without tracheostomy using nasal intermittent positive airway pressure. If the nerve to the diaphragm is intact, diaphragmatic pacing may be a viable alternative. If the paralysis occurs during open heart surgery, recovery frequently occurs, but it may take 6 months or more.

Unilateral paralysis of the diaphragm is much more common than is bilateral paralysis. The most common cause is nerve invasion from malignancy, usually a bronchogenic carcinoma. If the patient does not have malignancy, then usually no cause for the paralysis is found. The diagnosis is suggested by finding an elevated hemidiaphragm on the chest roentgenogram. Confirmation is best established with the "sniff test." When a patient is observed with fluoroscopy while sniffing, the paralyzed diaphragm will move paradoxically upward due to the negative intrathoracic pressure. Patients with a unilateral paralyzed diaphragm are usually asymptomatic. Their vital capacity and total lung capacity are each reduced about 25%. If a patient has a mediastinal mass in conjunction with the diaphragmatic paralysis, further workup should be done. However, if the patient is asymptomatic with a normal chest radiograph, no invasive procedures are warranted.

DISORDERS OF THE CHEST WALL

KYPHOSCOLIOSIS

Kyphoscoliosis is a combination of excessive anteroposterior and lateral curvature of the thoracic spine. Abnormalities of the spinal curvature are common, occurring in about 3% of the population. However, deformity of a sufficient degree to lead to symptoms and signs referable to the heart or lungs is rare, occurring in fewer than 3% of those with abnormal curvature. The major pathophysiologic effects of severe kyphoscoliosis are restrictive lung disease and ventilation-perfusion imbalances that result in chronic alveolar hypoventilation, hypoxic vasoconstriction, and eventually pulmonary arterial hypertension and cor pulmonale.

The severity of the cardiopulmonary disease correlates roughly with the degree of scoliosis. If the angle of curvature is 60°, ventilatory impairment is rare, while if it is 90°, marked ventilatory abnormalities develop commonly.

Although much effort has been devoted to restoring the normal curvature by either internal fixation or an external device, these efforts result in more improvement in the cosmetic appearance than in pulmonary function. However, the earlier that corrective actions are undertaken, the better the results. Once cardiorespiratory failure has developed, there is a high mortality from operative intervention. Patients with kyphoscoliosis and recurrent episodes of respiratory failure benefit from chronic nocturnal mechanical ventilation or nasal continuous positive airway pressure.

PECTUS EXCAVATUM (FUNNEL CHEST)

In this congenital condition, the lower portion of the sternum is displaced posteriorly and the anterior ribs are markedly bowed, which results in a depressed panel in the anterior chest. Respiratory symptoms are uncommon, and pulmonary function tests are nearly normal. Surgical correction is seldom indicated and then only to treat psychological upset resulting from the cosmetic deformity.

PECTUS CARINATUM (PIGEON BREAST)

This condition is the reverse of pectus excavatum with the sternum protruding anteriorly. This deformity is associated with congenital atrial or ventricular septal defects and severe prolonged childhood asthma. The deformity itself does not cause symptoms, and surgery is for cosmetic purposes only


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